Methods and compositions for topical delivery of prostaglandins to subcutaneous fat

ABSTRACT

Described herein are compositions comprising a prostaglandin FP receptor agonist (PFPRA) compound and a fatty acid, e.g., oleic acid, that, when topically applied to the skin, locally delivers a therapeutically effective amount of the PFPRA compound or active metabolite thereof to subcutaneous fat under the skin. The therapeutic effect is, for example, reduction of the subcutaneous fat under the skin. Further provided are methods of reducing body fat in a subject comprising topically administering the composition to the subject. The present invention also provides kits comprising the composition and instructions for use.

RELATED APPLICATIONS

This application is a continuation of and claims priority under 35U.S.C. § 120 to U.S. Application, U.S. Ser. No. 15/816,253, filed Nov.17, 2017; which is a continuation of and claims priority under 35 U.S.C.§ 120 to U.S. Application, U.S. Ser. No. 14/889,093, filed Nov. 4, 2015;which is a national stage filing under 35 U.S.C. § 371 of internationalPCT application, PCT/US2014/038067, filed May 15, 2014; which claimspriority under 35 U.S.C. § 119(e) to U.S. provisional patentapplication, U.S. Ser. No. 61/823,659, filed May 15, 2013; the entirecontents of each of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to methods and compositions for topicallydelivering a therapeutically effective amount of a prostaglandin FPreceptor agonist (a PFPRA compound) to adipocytes under the skin. ThePFPRA compound can be, for example, an analog of prostaglandin F2α. Thetherapeutic effect is, for example, reduction of excess fat under theskin, for example, excess subcutaneous fat of the face, neck, chin,submental region, limbs, breast, abdomen, hips, etc. More specifically,the invention relates to new compositions comprising a PFPRA compoundand a fatty acid (e.g., oleic acid) and optionally further comprisingone or more organic alcohols (e.g., ethanol and/or propylene glycol),and methods comprising applying the composition(s) to the skin.

Experimentally, in comparison to a wide array of other compositionstested, the compositions disclosed herein demonstrate exceptionalefficiency in delivering certain PFPRA compounds across skin in vitro,in delivering a therapeutically effective amount to adipose tissue invivo, and/or in reducing subcutaneous fat in vivo. In theory, thisefficiency may owe to the similar structure and polarity between thePFPRA compound (e.g., latanoprost) or an active metabolite thereof(e.g., latanoprost free acid) and the fatty acid (e.g., oleic acid), asdescribed herein. The compositions are well-tolerated, non-irritating,and aesthetically pleasing. Furthermore, the compositions are physicallyand chemically stable and readily manufactured.

BACKGROUND OF THE INVENTION

Excess body fat is an important cause of human disease, disability, andcosmetic disturbance. For many people excess body fat is also a sourceof psychosocial distress and reduced self-esteem.

Excess body fat may be diffuse or concentrated on particular portion(s)of the body. Of particular importance is excess body fat of the face,for example, of the eyelids, chin, or jowls. Other important sites ofexcess body fat can include, for example, the arms, abdomen, buttocks,hips, chest, thighs, and neck. Excess body fat can also involveexcessive breast tissue on a woman or on a man, i.e., gynecomastia.Excess body fat can be located within or near the eyelids, and topicaltreatment of such fat requires a composition that is safe forapplication near the eyes, i.e. an ophthalmic and/or ophthalmicallycompatible formulation. Local accumulations of body fat may result fromconstitutional factors, disease, hormonal status, or as side effects ofmedication or other substances. Even in the absence of disease, cosmeticconsiderations apply to individuals who nevertheless perceive an excessof fat and wish to have it corrected. For example, excess submental fat,commonly known as “double chin,” is not considered a disease; however,people with excess submental fat often appear less attractive and lessyouthful, and can have lower self-esteem as a result. Likewise, anindividual may have excess subcutaneous fat on the anterior abdomen,excess subcutaneous fat on the oblique abdomen, e.g. above the iliaccrests (“love handles”), excess chest fat, excess breast fat, excessbuttocks fat, excess hip fat, excess thigh fat, excess leg fat, excessupper arm fat, excess check fat, excess neck fat, etc.

A number of medical conditions are considered to be causes of excessbody fat. Examples include drug-induced obesity, hypothyroidism,pseudohypoparathyroidism, hypothalamic obesity, polycystic ovariandisease, depression, binge eating, Prader-Willi syndrome, Bardet-Biedlsyndrome, Cohen syndrome, Down syndrome, Turner syndrome, growth hormonedeficiency, growth hormone resistance, and leptin deficiency orresistance. Disfiguring excess regional fat deposits, for example excessdorsocervical fat, may be found in conditions such as HIV lipodystrophy,Cushing syndrome and pseudo-Cushing syndrome (i.e., characteristicsyndrome of excess body fat and other findings due to excessiveendogenous or exogenous corticosteroid levels), other acquiredlipodystrophies, familial lipodystrophies, lipoma, lipomatosis, andMadelung disease.

Medications known to cause excess body fat include cortisol and analogs,other corticosteroids, megace, sulfonylureas, antiretrovirals, tricyclicantidepressants, monoamine oxidase inhibitors, selective serotoninreuptake inhibitors, oral contraceptives, insulin, risperidone,clozapine, and thiazolidinediones.

Changes in hormonal status, including physiologic changes such aspregnancy or menopause, may result in excess body fat in a subject.Smoking cessation commonly leads to weight gain and excess body fat.Trauma may favor the accumulation of excess body fat by virtue ofimmobility or disuse of an extremity. Similar problems may affect asubject who is immobilized, for example due to an injury. Some tumors,for example lipomas and liposarcomas, are characterized by localcollections of fat cells. Lipomatosis is any condition characterized bythe formation of multiple lipomas on the body, e.g., familial multiplelipomatosis, adiposis dolorosis (Dercum's disease), pelvic lipomatosis,etc.

Even in the absence of underlying pathology, an individual may havecosmetic concerns about local or diffuse deposits of body fat. These canusually be attributed to constitutional or hereditary factors,developmental history, age, gender, diet, alcohol use, or othercomponents of lifestyle. Individuals in such circumstances commonly wishto reduce the amount of fat on the face, eyelids, chin, arms, neck,abdomen, chest, breast, buttocks, hips, thighs, and/or legs. In somecases a local excess of fat can be due to fat prolapse, displacement,and/or migration, as in age-related orbital fat prolapse or descent ofmalar fat pads. Grave's ophthalmopathy (thyroid-releated eye disease) isa condition that can be treated by reducing the volume of orbital fat.

A number of methods have been developed to reduce or remove excess bodyfat. It is helpful to classify these methods as extractive, metabolic,or adipolytic. Extractive methods, such as lipoplasty (e.g.,liposuction) or local excision, are methods whereby fat is physicallyremoved from areas of interest. Such methods are costly and may involvescars, postsurgical deformity or regression, discomfort, infection, andother adverse reactions.

In contrast to extractive methods, metabolic methods, which includesystemic medications, nutritional supplements, devices, and exercise orother body treatment, seek to modify the subject's metabolism (e.g.,whether caloric consumption, expenditure, or both) such that the subjectincurs a net loss of fat. A disadvantage is that these methods typicallycannot be directed to a particular part of the body. Another drawback ispotential concomitant loss of water, carbohydrates, protein, vitamins,minerals, and other nutrients. Furthermore, traditional diet medicationsmay have undesired side effects, for example palpitations, tremor,insomnia, and/or irritability in a subject who uses stimulants asappetite suppressants. Despite salubrious value, the traditionalmetabolic methods of diet and exercise are not practical for everybody.

Adipolytic methods aim to cause breakdown of adipocytes and/or theirlipid contents. For example, fat deposits can be reduced by exposure tocold temperature or to deoxycholate, a solubilizer that lyses cellmembranes and results in local necrosis. Drawbacks of these methods caninclude poor discrimination between adipose and other nearby tissues,barriers to delivery that require hypodermic needles or specialequipment, and adverse effects such as necrosis, inflammation, and pain.

Compounds of the prostaglandin FP receptor agonist (PFPRA compound)class, e.g., latanoprost and tafluprost, can be administered to the skinto locally reduce adipose tissue under the skin, i.e., subcutaneous fat.See, e.g., U.S. Pat. No. 8,426,471 and U.S. Publication No.2010/0234466, incorporated herein by reference. Developing topicaldelivery of the PFPRA compound poses significant challenges, sincedelivery to subcutaneous fat comprises delivery across the stratumcorneum, epidermis, dermis, and dermal microcirculation, and into thefat below.

For example, the skin, in particular the stratum corneum, presents aformidable physical barrier to drug penetration. See, e.g., Dayan N,Delivery System Design in Topically Applied Formulations: An Overview,in Rosen M, Delivery System Handbook for Personal Care and CosmeticProducts, William Andrew, 2005, pp. 103-104. For any particular drug,the formulation must be selected empirically. The formulation must bephysically and chemically compatible with the drug.

Furthermore, provided that a formulation enables a drug to cross theskin, to reach the subcutaneous fat it must also circumvent what isknown as the “sink condition” of the dermal circulation. See, e.g.,Dayan N, Delivery System Design in Topically Applied Formulations: AnOverview, in Rosen M, Delivery System Handbook for Personal Care andCosmetic Products, William Andrew, 2005, pp. 103-104; Kao J, In VitroAssessment of Dermal Absorption, in Hobson D W, Dermal and OcularToxicology: Fundamentals and Methods, CRC Press, 1991, pp. 272-273.Because the dermis is invested by a network of capillaries with rapidblood flow, for any solute (e.g., drug) that penetrates the dermis, awide concentration gradient is created between the skin and bloodstream.Thus, there is a strong tendency for drugs that penetrate into thedermis to diffuse rapidly down this gradient into the bloodstream. Thissink phenomenon favors systemic delivery (e.g., to the bloodstream, aswith a nicotine patch), but undermines attempts at local delivery (e.g.,to subcutaneous fat, as in the present invention). No method ofreasoning or prediction is available in the art to suggest whichformulations, if any, can circumvent the sink condition. Therefore, theartisan must search for such formulations empirically, and without priorknowledge that such formulation even exists.

The formulation must also have a favorable systemic drug exposureprofile, e.g., that avoids excessive levels of drug in the bloodstream.This requirement is rendered more difficult by the sink condition.

Additionally, the formulation should deliver the active ingredient withreasonable efficiency. One measure of efficiency is the ability tominimize the concentration of active ingredient in the finished productand still maintain the desired therapeutic effect. This has implicationsfor manufacturability, cost of goods, and local safety and tolerability.Another measure of efficiency is the ability to minimize the dosefrequency and still maintain the desired therapeutic effect, which hasimplications for patient convenience and product marketability.

As well, the formulation must cause little or no skin irritation. Ifapplied to skin near the eye, e.g., the eyelid, the formulation isconsidered an ophthalmic formulation. Generally, an ophthalmicformulation must be sterile, e.g., according to Chapter <71> of the U.S.Pharmacopeia. Preferably, an ophthalmic formulation must also be free oressentially free of bacterial endotoxin, e.g. according to Chapter <85>of the U.S. Pharmacopeia, e.g., an endotoxin level of <10 EU (endotoxinunits) per gram of composition. If applied to skin near the eye, theformulation must be ophthalmically compatible, i.e, the formulation mustnot cause clinically significant eye irritation, and must not be toxicto the eye, e.g., the ocular surface, e.g. the cornea. Irritationpotential and ocular toxicity are studied empirically by standardpreclinical models, or in human trials. Although the skin or eyeirritation potential of individual inactive ingredients is generallyknown, combinations of inactive and active ingredients can causeunexpected irritation, which must be tested empirically.

Furthermore, the formulation must possess other qualities necessary tomake a topical formulation and market it to consumers: ease ofmanufacture, physical and chemical stability, and commerciallyacceptable appearance, odor, and tactile qualities.

Therefore, there is a need for new compositions for topically deliveringa PFPRA compound to adipose tissue under the skin.

SUMMARY OF THE INVENTION

It has now been discovered experimentally that certain compositionscomprising, e.g., latanoprost and a fatty acid (e.g., oleic acid)provide exceptionally efficient delivery of the latanoprost and itsactive metabolite into subcutaneous fat, and thus have particular usesand advantages, as described herein. In theory, this efficiency may oweto the similar structure and polarity between the PFPRA compound (e.g.,latanoprost) or active metabolite thereof (e.g., latanoprost free acid)and the fatty acid (e.g., oleic acid), as described herein. For example,it has been discovered that compositions comprising latanoprost incombination with oleic acid provide efficient delivery of the activemetabolite of latanoprost (latanoprost free acid) into the subcutaneousfat. This may relate to the fact that latanoprost hydrolyzes to theactive metabolite (latanoprost free acid) in the skin. See, e.g.,Example 4. The therapeutic effect of this delivery is reduction ofsubcutaneous fat.

Thus, in one aspect, provided is a composition comprising a PFPRAcompound, e.g., latanoprost or tafluprost and a fatty acid, e.g., oleicacid, e.g., useful in the reduction of subcutaneous fat. In certainembodiments, the concentration of the PFPRA compound in the compositionis between about 0.0001 percent to about 1 percent by weight, inclusive,e.g., between about 0.05 percent and about 0.5 percent by weight, orbetween about 0.01 percent and about 0.1 percent by weight, of the totalweight of the composition. In some embodiments, the final concentrationof the fatty acid is between about 1 percent to about 20 percent byweight, inclusive, e.g., between about 1 percent and about 5 percent byweight, or between about 2 percent and about 4 percent by weight, of thetotal weight of the composition. In some embodiments, the compositionfurther comprises one or more organic alcohols (e.g., ethanol and/orpropylene glycol). In some embodiments, the final concentration of anorganic alcohol is between about 5 percent and about 99 percent,inclusive, by weight of the total weight of the composition. In certainembodiments, the final concentration of an organic alcohol (e.g.,propylene glycol) between about 5 percent and about 50 percent,inclusive, by weight of the total weight of the composition, e.g.,between about 20 percent and about 30 percent by weight, or betweenabout 25 percent and about 30 percent by weight, of the total weight ofthe composition. In certain embodiments, the final concentration of anorganic alcohol (e.g., ethanol) between about 60 percent and about 80percent, inclusive, by weight of the total weight of the composition. Incertain embodiments, the composition comprises about 3 percent of afatty acid (e.g., oleic acid) and one or more organic alcohols (e.g.,27% of propylene glycol and/or 65%-70% of ethanol) by weight of thetotal weight of the composition. In some embodiments, the compositionfurther comprises water. In some embodiments, the composition furthercomprises glycerin. In certain embodiments, the composition is for usein reducing body fat in a subject. In certain embodiments, thecomposition is used in the manufacture of a medicament for reducing bodyfat in a subject.

In another aspect, provided is a method of reducing body fat in asubject, comprising topically administering a composition as describedherein to a subject in need thereof. In yet another aspect, provided isa kit comprising a composition as described herein and instructions foruse.

Other objects and advantages will become apparent to those skilled inthe art from consideration of the ensuing Detailed Description,Examples, and Claims.

DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts three-dimensional molecular models of oleic acid andlatanoprost free acid in energy-minimized conformations (solved invacuo). Carbon atoms are shown in gray and oxygen atoms in red;hydrogens are not shown. Measured end-to-end distances (between heavyatom centers) are 19.1 Å for oleic acid and 17.1 Å for latanoprost freeacid.

DEFINITIONS Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Certain compounds as described herein can comprise one or moreasymmetric centers, and thus can exist in various isomeric forms, e.g.,enantiomers and/or diastereomers. The compounds provided herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer. Incertain embodiments, the compounds as described herein are enantiopurecompounds. In certain other embodiments, mixtures of stereoisomers areprovided.

Furthermore, certain compounds, as described herein may have one or moredouble bonds that can exist as either the cis or trans, or the E or Zisomer, unless otherwise indicated. The invention additionallyencompasses the compounds as individual isomers substantially free ofother isomers, and alternatively, as mixtures of various isomers, e.g.,racemic mixtures of E/Z isomers or mixtures enriched in one E/Z isomer.

The terms “enantiomerically enriched,” “enantiomerically pure” and“non-racemic,” as used interchangeably herein, refer to compositions inwhich the percent by weight of one enantiomer is greater than the amountof that one enantiomer in a control mixture of the racemic composition(e.g., greater than 1:1 by weight). For example, an enantiomericallyenriched preparation of the (S)-enantiomer, means a preparation of thecompound having greater than 50% by weight of the (S)-enantiomerrelative to the (R)-enantiomer, more preferably at least 75% by weight,and even more preferably at least 80% by weight. In some embodiments,the enrichment can be much greater than 80% by weight, providing a“substantially enantiomerically enriched,” “substantiallyenantiomerically pure” or a “substantially non-racemic” preparation,which refers to preparations of compositions which have at least 85% byweight of one enantiomer relative to other enantiomer, more preferablyat least 90% by weight, and even more preferably at least 95% by weight.In preferred embodiments, the enantiomerically enriched composition hasa higher potency with respect to therapeutic utility per unit mass thandoes the racemic mixture of that composition. Enantiomers can beisolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred enantiomerscan be prepared by asymmetric syntheses. See, for example, Jacques, etal., Enantiomers, Racemates and Resolutions (Wiley Interscience, NewYork, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); andWilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein, “aliphatic” refers to an alkyl, alkenyl, alkynyl, orcarbocyclyl group, as defined herein.

As used herein, alone or as part of another group, “alkyl” refers to aradical of a straight-chain or branched saturated hydrocarbon grouphaving from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). In some embodiments,an alkyl group has 1 to 10 carbon atoms (“C₁₋₁₀ alkyl”). In someembodiments, an alkyl group has 1 to 6 carbon atoms (“C₁₋₆ alkyl”). Insome embodiments, an alkyl group has 1 to 5 carbon atoms (“C₁₋₅ alkyl”).In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C₁₋₄alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms(“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1 to 2 carbonatoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl group has 1 carbonatom (“C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbonatoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groups include methyl (C₁),ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl(C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅),amyl (C₅), neopentyl (C₆), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅),and n-hexyl (C₆). Unless otherwise specified, each instance of an alkylgroup is independently unsubstituted (an “unsubstituted alkyl”) orsubstituted (a “substituted alkyl”) are substituted with one or moresubstituents. In certain embodiments, the alkyl group is anunsubstituted C₁₋₆ alkyl (e.g., —CH₃). In certain embodiments, the alkylgroup is a substituted C₁₋₆ alkyl.

As used herein “perhaloalkyl” or “halosubstituted alkyl” as definedherein refers to an alkyl group having from 1 to 10 carbon atoms whereinall of the hydrogen atoms are each independently replaced halogen, e.g.,selected from fluoro, bromo, chloro or iodo (“C₁₋₁₀ perhaloalkyl”). Insome embodiments, the alkyl moiety has 1 to 6 carbon atoms (“C₁₋₆perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 5 carbonatoms (“C₁₋₅ perhaloalkyl 1”). In some embodiments, the alkyl moiety has1 to 4 carbon atoms (“C₁₋₄ perhaloalkyl”). In some embodiments, thealkyl moiety has 1 to 3 carbon atoms (“C₁₋₃ perhaloalkyl”). In someembodiments, the alkyl moiety has 1 to 2 carbon atoms (“C₁₋₂perhaloalkyl”). In some embodiments, all of the hydrogen atoms are eachreplaced with fluoro. In some embodiments, all of the hydrogen atoms areeach replaced with chloro. Examples of perhaloalkyl groups include —CF₃,—CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl and the like.

As used herein, “alkyloxy” refers to an alkyl group, as defined herein,substituted with an oxygen atom, wherein the point of attachment is theoxygen atom. In certain embodiments, the alkyl group has 1 to 6 carbonatoms (“C₁₋₆ alkyloxy”). In some embodiments, the alkyl group has 1 to 4carbon atoms (“C₁₋₄ alkyloxy”). Examples of C₁₋₄ alkyloxy groups includemethoxy (C₁), ethoxy (C₂), propoxy (C₃), isopropoxy (C₃), butoxy (C₄),tert-butoxy (C₅) and the like. Examples of C₁₋₆ alkyloxy groups includethe aforementioned C₁₋₄ alkyloxy groups as well as pentyloxy (C₅),isopentyloxy (C₅), neopentyloxy (C₅), hexyloxy (C₆) and the like. Unlessotherwise specified, each instance of the alkyl moiety of the alkyloxygroup is independently unsubstituted (an “unsubstituted alkyloxy”) orsubstituted (a “substituted alkyloxy”) with one or more substituents. Incertain embodiments, the alkyloxy group is an unsubstituted C₁₋₆alkyloxy. In certain embodiments, the alkyloxy group is a substitutedC₁₋₆ alkyloxy.

As used herein, “alkylcarboxy” refers to a group of the formula—C(═O)OR^(a) wherein Ra is an alkyl group as defined herein. In certainembodiments, the alkyl of the alkylcarboxy group has 1 to 6 carbon atoms(“C₁₋₆ alkylcarboxy”). In some embodiments, the alkyl of thealkylcarboxy group has 1 to 5 carbon atoms (“C₁₋₅ alkylcarboxy”). Insome embodiments, the alkyl of the alkylcarboxy group has 1 to 4 carbonatoms (“C₁₋₄ alkylcarboxy”). In some embodiments, the alkyl of thealkylcarboxy group has 1 to 3 carbon atoms (“C₁₋₃ alkylcarboxy”). Insome embodiments, the alkyl of the alkylcarboxy group has 1 to 2 carbonatoms (“C₁₋₂ alkylcarboxy”). Unless otherwise specified, each instanceof the alkyl of the alkylcarboxy group is independently unsubstituted(an “unsubstituted alkylcarboxy”) or substituted (a “substitutedalkylcarboxy”) with one or more substituents. In certain embodiments,the alkylcarboxy group is an unsubstituted C₁₋₆ alkylcarboxy. In certainembodiments, the alkylcarboxy group is a substituted C₁₋₆ alkylcarboxy.

As used herein, alone or as part of another group, “alkenyl” refers to aradical of a straight-chain or branched hydrocarbon group having from 2to 20 carbon atoms and one or more carbon-carbon double bonds (“C₂₋₂₀alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbonatoms (“C₂₋₁₀ alkenyl”). In some embodiments, an alkenyl group has 2 to6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl grouphas 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, analkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In someembodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”).In some embodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”).The one or more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄) and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆) and the like. Unlessotherwise specified, each instance of an alkenyl group is independentlyunsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is an unsubstituted C₂₋₆ alkenyl. Incertain embodiments, the alkenyl group is a substituted C₂₋₆ alkenyl.

As used herein, alone or as part of another group, “alkynyl” refers to aradical of a straight-chain or branched hydrocarbon group having from 2to 20 carbon atoms and one or more carbon-carbon triple bonds (“C₂₋₂₀alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbonatoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl group has 2 to6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In some embodiments, analkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”). In someembodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃ alkynyl”).In some embodiments, an alkynyl group has 2 carbon atom (“C₂ alkynyl”).The one or more carbon-carbon triple bonds can be internal (such as in2-butynyl) or terminal (such as in 1-butynyl). Examples of C₂₋₄ alkynylgroups include, without limitation, ethynyl (C₂), 1-propynyl (C₃),2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄) and the like. Examplesof C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkynyl groups aswell as pentynyl (C₅), hexynyl (C₆) and the like. Unless otherwisespecified, each instance of an alkynyl group is independentlyunsubstituted (an “unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents. In certainembodiments, the alkynyl group is an unsubstituted C₂₋₆ alkynyl. Incertain embodiments, the alkynyl group is a substituted C₂₋₆ alkynyl.

As used herein, a “saturated or unsaturated acyclic hydrocarbon” refersto radical of a saturated or unsaturated, straight-chain or branched,hydrocarbon group having from 1 to 20 carbon atoms and optionally one ormore carbon-carbon double or triple bonds. In certain embodiments, thehydrocarbon group is saturated. In some embodiments, the hydrocarbongroup is unsaturated, and contains one or more carbon-carbon double ortriple bonds. In some embodiments, the hydrocarbon group contains 1-10carbon atoms. In certain embodiments, the hydrocarbon group contains 1-5carbon atoms. In some embodiments, the hydrocarbon group contains 1-4carbon atoms. In some embodiments, the hydrocarbon group contains 1-3carbon atoms. In some embodiments, the hydrocarbon group contains 1-2carbon atoms.

As used herein, “carbocyclyl” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 7 ring carbon atoms (“C₃₋₇carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms(“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Exemplary C₃₋₇ carbocyclylgroups include, without limitation, cyclopropyl (C₃), cyclopropenyl(C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅),cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl(C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇),cycloheptatrienyl (C₇), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing afused, bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”)) and can be saturated or can contain one or morecarbon-carbon double or triple bonds. “Carbocyclyl” also includes ringsystems wherein the carbocyclyl ring, as defined above, is fused withone or more aryl or heteroaryl groups wherein the point of attachment ison the carbocyclyl ring, and in such instances, the number of carbonscontinue to designate the number of carbons in the carbocyclic ringsystem. Unless otherwise specified, each instance of a carbocyclyl groupis independently unsubstituted (an “unsubstituted carbocyclyl”) orsubstituted (a “substituted carbocyclyl”) with 1, 2, 3, 4, or 5substituents as described herein. In certain embodiments, thecarbocyclyl group is an unsubstituted C₃₋₁₀ carbocyclyl. In certainembodiments, the carbocyclyl group is a substituted C₃₋₁₀ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 7 ring carbon atoms (“C₃₋₇cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 5 to 6 ring carbon atoms (“C₅₋₆ cycloalkyl”). Examples of C₅₋₆cycloalkyl groups include cyclopentyl (C₅) and cyclohexyl (C₅). Examplesof C₃₋₆ cycloalkyl groups include the aforementioned C₅₆ cycloalkylgroups as well as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₇cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇). Unless otherwise specified, each instance of acycloalkyl group is independently unsubstituted (an “unsubstitutedcycloalkyl”) or substituted (a “substituted cycloalkyl”) with one ormore substituents. In certain embodiments, the cycloalkyl group is anunsubstituted C₃₋₇ cycloalkyl. In certain embodiments, the cycloalkylgroup is a substituted C₃₋₇ cycloalkyl.

As used herein, alone or as part of another group, “heterocyclyl” refersto a radical of a 3- to 8-membered non-aromatic ring system having ringcarbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom isindependently selected from nitrogen, oxygen and sulfur (“3-8-memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic heterocyclyl”)),and can be saturated or can contain one or more carbon-carbon double ortriple bonds. Heterocyclyl polycyclic ring systems can include one ormore heteroatoms in one or both rings. “Heterocyclyl” also includes ringsystems wherein the heterocycyl ring, as defined above, is fused withone or more carbocycyl groups wherein the point of attachment is eitheron the carbocycyl or heterocyclyl ring, or ring systems wherein theheterocyclyl ring, as defined above, is fused with one or more aryl orheteroaryl groups, wherein the point of attachment is on theheterocyclyl ring, and in such instances, the number of ring memberscontinue to designate the number of ring members in the heterocyclylring system.

In some embodiments, a heterocyclyl group is a 5-8 membered non-aromaticring system having ring carbon atoms and 1-4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen andsulfur (“5-8-membered heterocyclyl”). In some embodiments, aheterocyclyl group is a 5-6-membered non-aromatic ring system havingring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom isindependently selected from nitrogen, oxygen and sulfur (“5-6-memberedheterocyclyl”). In some embodiments, the 5-6-membered heterocyclyl has1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In someembodiments, the 5-6-membered heterocyclyl has 1-2 ring heteroatomsselected from nitrogen, oxygen and sulfur. In some embodiments, the5-6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen,oxygen and sulfur. Exemplary 3-membered heterocyclyls containing 1heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.Exemplary 4-membered heterocyclyls containing 1 heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyls containing 1 heteroatom include, withoutlimitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclyls containing 2 heteroatoms include,without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary5-membered heterocyclyls containing 3 heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing 1 heteroatom include, withoutlimitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, andthianyl. Exemplary 6-membered heterocyclyl groups containing 2heteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing2 heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing 1 heteroatom include, withoutlimitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,azocanyl, oxecanyl and thiocanyl. Unless otherwise specified, eachinstance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is an unsubstituted 3-8-membered heterocyclyl. Incertain embodiments, the heterocyclyl group is a substituted3-8-membered heterocyclyl.

As used herein, alone or as part of another group, “aryl” refers to aradical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2aromatic ring system having 6-10 ring carbon atoms and zero heteroatomsprovided in the aromatic ring system (“C₆₋₁₀ aryl”). In someembodiments, an aryl group has 6 ring carbon atoms (“C₆ aryl”; e.g.,phenyl). In some embodiments, an aryl group has 10 ring carbon atoms(“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). “Aryl”also includes ring systems wherein the aryl ring, as defined above, isfused with one or more cycloalkyl or heterocyclyl groups wherein theradical or point of attachment is on the aryl ring, and in suchinstances, the number of carbon atoms continue to designate the numberof carbon atoms in the aryl ring system. Unless otherwise specified,each instance of an aryl group is independently unsubstituted (an“unsubstituted aryl”) or substituted (a “substituted aryl”) with one ormore substituents as described herein. In certain embodiments, the arylgroup is an unsubstituted C₆₋₁₀ aryl. In certain embodiments, the arylgroup is a substituted C₆₋₁₀ aryl.

As used herein, alone or as part of another group, “heteroaryl” refersto a radical of a 5-14-membered monocyclic or polycyclic (e.g.,bicyclic) 4n+2 aromatic ring system having 4-10 ring carbon atoms and1-4 ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10-membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl polycyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocycyl or heterocycyl groups wherein the point of attachmentis on the heteroaryl ring, and in such instances, the number of ringmembers continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl or on theheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused polycyclic(aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein onering does not contain a heteroatom (e.g., indolyl, quinolinyl,carbazolyl and the like) the point of attachment can be on either ring,i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ringthat does not contain a heteroatom (e.g., 5-indolyl). In someembodiments, a heteroaryl group is a 5-10-membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-10-membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8-membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-8-membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6-membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-6-membered heteroaryl”). In someembodiments, the 5-6-membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen and sulfur. In some embodiments, the5-6-membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen and sulfur. In some embodiments, the 5-6-membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen and sulfur. Exemplary5-membered heteroaryls containing 1 heteroatom include, withoutlimitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-memberedheteroaryls containing 2 heteroatoms include, without limitation,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryls containing 3 heteroatomsinclude, without limitation, triazolyl, oxadiazolyl, thiadiazolyl.Exemplary 5-membered heteroaryls containing 4 heteroatoms include,without limitation, tetrazolyl. Exemplary 6-membered heteroarylscontaining 1 heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryls containing 2 heteroatoms include,without limitation, pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary6-membered heteroaryls containing 3 or 4 heteroatoms include, withoutlimitation, triazinyl and tetrazinyl, respectively. Exemplary 7 memberedheteroaryls containing 1 heteroatom include, without limitation,azepinyl, oxepinyl and thiepinyl. Exemplary 5,6-bicyclic heteroarylsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include,without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.Unless otherwise specified, each instance of a heteroaryl group isindependently unsubstituted (an “unsubstituted heteroaryl”) orsubstituted (a “substituted heteroaryl”) with one or more substituents.In certain embodiments, the heteroaryl group is an unsubstituted5-10-membered heteroaryl. In certain embodiments, the heteroaryl groupis a substituted 5-10-membered heteroaryl.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl, referred to without the suffix “-ene,” describe amonoradical of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,or heteroaryl, respectively, and as defined herein, wherein themonoradical is directly attached to a parent molecule or to anothergroup by one bond (e.g., one single or double bond). Monoradical groups,as defined herein, may also be optionally substituted. Groups referredto with the suffix “-ene”, such as alkylene, alkenylene, alkynylene,carbocyclylene, heterocyclylene, arylene and heteroarylene groups,describe a diradical of alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, respectively, and as defined herein,wherein the diradical is between and directly attached to two groups(e.g., between the parent molecule and another group) by two bonds(e.g., single or double bonds). Diradical groups may also be optionallysubstituted.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group (e.g., 1, 2, 3, 4, or 5 positions), and when morethan one position in any given structure is substituted, the substituentis either the same or different at each position. The term “substituted”is contemplated to include substitution with all permissiblesubstituents of organic compounds, any of the substituents describedherein that results in the formation of a stable compound. The presentinvention contemplates any and all such combinations in order to arriveat a stable compound. For purposes of this invention, heteroatoms suchas nitrogen may have hydrogen substituents and/or any suitablesubstituent as described herein which satisfy the valencies of theheteroatoms and results in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(OR^(cc))R^(bb), —SH, —SR—, —SSR^(cc), —C(═O)R^(aa),—CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa), —OC(═O)R^(aa), —OCO₂R^(aa),—C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂, —NR^(bb)C(═O)R^(aa),—NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —SC(═O)OR^(aa), —OC(═O)SR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R′)₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇carbocyclyl, 3-8-membered heterocyclyl, C₆₋₁₀ aryl, and 5-10-memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R—, ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8-membered heterocyclyl,C₆₋₁₀ aryl, and 5-10-membered heteroaryl, or two R^(aa) groups arejoined to form a 3-8-membered heterocyclyl or 5-10-membered heteroarylring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups; each instance of R^(bb) is, independently, selectedfrom hydrogen, —OH, —OR^(a), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(aa),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(aa))₂, —P(═O)(NR^(cc))₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8-memberedheterocyclyl, C₆₋₁₀ aryl, and 5-10-membered heteroaryl, or two R^(bb)groups are joined to form a 3-8-membered heterocyclyl or 5-10-memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 Rad groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8-memberedheterocyclyl, C₆₋₁₀ aryl, and 5-10-membered heteroaryl, or two R^(aa)groups are joined to form a 3-8-membered heterocyclyl or 5-10-memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 Rad groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee), —C(═O)R^(ee), —CO₂H,—C(═O)OR^(ee), —OC(═O)R^(ee), —OC(═O)OR^(ee), —C(═O)N(R^(ff))₂,—OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee), —NR^(ff)CO₂R^(ee),—NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee),—OC(═NR^(ff))OR^(ee), —C(═NR^(ee))N(R)N(R)₂,—NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ee))₂,—SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃,—OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee),—SC(═S)SR^(ee), —P(═O)₂R^(ee), —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂,—OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇carbocyclyl, 3-8-membered heterocyclyl, C₆₋₁₀ aryl, and 5-10-memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups, or two geminal R^(dd) substituents canbe joined to form ═O or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8-membered heterocyclyl,C₆₋₁₀ aryl, and 5-10-membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8-memberedheterocyclyl, C₆₋₁₀ aryl, and 5-10-membered heteroaryl, or two R^(f)groups are joined to form a 3-8-membered heterocyclyl or 5-10-memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl),—OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂,—OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl),—OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl),—C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,3-8-membered-heterocyclyl, C₆₋₁₀ aryl, and 5-10-membered heteroaryl; ortwo geminal R^(gg) substituents can be joined to form ═O or ═S.

In certain embodiments, the carbon atom substituent is selected from thegroup consisting of halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH,—OR^(aa), —N(R^(b))₂, —SH, —SR^(aa), —C(═O)R^(aa), —CO₂H, —CHO,—CO₂R^(aa), —OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂,—OC(═O)N(R^(bb))₂, —NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa),—NR^(bb)C(═O)N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa), —NR^(bb)SO₂R^(aa),—SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —S(═O)R^(aa), —OS(═O)R^(aa),—Si(R^(aa))₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,3-8-membered heterocyclyl, C₆₋₁₀ aryl, and 5-10-membered heteroaryl,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Radgroups;

As used herein, the term “hydroxyl” or “hydroxy” refers to the group—OH. The term “substituted hydroxyl” or “substituted hydroxy,” byextension, refers to a hydroxyl group wherein the oxygen atom issubstituted with a group other than hydrogen, e.g., selected from—OR^(aa), —ON(R^(bb))₂, —OC(═O)R^(aa), —OC(═O)SR^(aa), —OCO₂R^(aa),—OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa),—OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa), —OSO₂R^(aa), —OSi(R^(aa))₃,—OP(R^(aa))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa), —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and —OP(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein.

As used herein, the term “thiol” or “thio” refers to the group —SH. Theterm “substituted thiol” or “substituted thio,” by extension, refers toa thiol group wherein the sulfur atom is substituted with a group otherthan hydrogen, and includes groups selected from —SR^(aa), —S═SR,—SC(═S)SR^(aa), —SC(═O)SR^(aa), —SC(═O)OR^(aa), and —SC(═O)R^(aa),wherein R^(aa) and R^(cc) are as defined herein.

As used herein, the term, “amino” refers to the group —NH₂.

As used herein, the term “substituted amino” refers to amonosubstituted, disubstituted, or trisubstituted amino group, asdefined herein.

As used herein, the term “monosubstituted amino” refers to an aminogroup substituted with one hydrogen and one group other than hydrogen,and includes groups selected from —NH(R^(bb)), —NHC(═O)R^(aa),—NHCO₂R^(aa), —NHC(═O)N(R^(bb))₂, —NHC(═NR^(bb))N(R^(bb))₂,—NHSO₂R^(aa), —NHP(═O)(OR^(aa))₂, and —NHP(═O)(NR^(bb))₂, whereinR^(aa), R^(bb) and R^(aa) are as defined herein, and wherein R^(bb) ofthe group —NH(R^(bb)) is not hydrogen.

As used herein, the term “disubstituted amino” refers to an amino groupsubstituted with two groups other than hydrogen, and includes groupsselected from —N(R^(bb))₂, —NR^(bb) C(═O)R^(aa), —NR^(bb)CO₂R^(aa)—,—NR^(bb)C(═O)N(R^(bb))₂, —NR^(bb)C(═NR^(bb))N(R^(bb))₂,—NR^(bb)SO₂R^(aa), —NR^(bb)P(═O)(OR^(aa))₂, and —NR^(bb)P(═O)(NR^(bb))₂,wherein R^(aa), R^(bb), and R^(aa) are as defined herein, with theproviso that the nitrogen atom directly attached to the parent moleculeis not substituted with hydrogen.

As used herein, the term “sulfonyl” refers to a group selected from—S(═O)₂OH, —S(═O)₂N(R^(bb))₂, —S(═O)₂R^(aa), and —S(═O)₂OR^(aa), whereinR^(aa) and R^(bb) are as defined herein.

As used herein, the term “sulfinyl” refers to —S(═O)OH and —S(═O)R^(aa),wherein R^(aa) is as defined herein.

As used herein, the term “carbonyl” refers a group wherein the carbondirectly attached to the parent molecule is sp² hybridized, and issubstituted with an oxygen, nitrogen or sulfur atom, e.g., a groupselected from ketones (—C(═O)R^(aa)), carboxylic acids (—CO₂H),aldehydes (—CHO), esters (—CO₂R^(aa), —C(═O)SR^(aa), —C(═S)SR^(aa)),amides (—C(═O)N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa), —C(═S)N(R^(bb))₂), andimines (—C(═NR^(bb))R^(aa)—, —C(═NR^(bb))OR^(aa)),—C(═NR^(bb))N(R^(bb))₂), wherein R^(aa) and R^(bb) are as definedherein.

As used herein, the term “silyl” refers to the group —Si(R^(aa))₃,wherein R^(aa) is as defined herein.

As used herein, the term “boronyl” refers to boranes, boronic acids,boronic esters, borinic acids, and borinic esters, e.g., boronyl groupsof the formula —B(R)₂, —B(OR^(aa))₂, and —BR^(aa)(OR^(aa)), whereinR^(aa) and R^(aa) are as defined herein.

As used herein, the term “phosphino” refers to the group —P(R^(aa))₃,wherein R^(aa) is as defined herein. An exemplary phosphino group istriphenylphosphine.

As used herein, the term “halo” or “halogen” refers to fluorine (fluoro,—F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

As used herein, “nitro” refers to the group —NO₂.

As used herein, “cyano” refers to the group —CN.

As used herein, “azido” refers to the group —N₃.

As used herein, “oxo” refers to the group ═O.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substitutents include, but are notlimited to, hydrogen, —OH, —OR^(aa), —N(R^(aa))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(aa))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NRC)N(R^(cc))₂, —SO₂N(R^(aa))₂, —SO₂R^(aa),—SO₂OR^(aa), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(aa))₂, —P(═O)(NR^(aa))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to an N atom are joined toform a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(aa) and R^(dd) are asdefined above.

In certain embodiments, the substituent present on the nitrogen atom isan “amino protecting group”. Amino protecting groups include, but arenot limited to, —OH, —OR^(aa), —N(R^(aa))₂, —C(═O)R^(aa),—C(═O)N(R^(aa))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(aa))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(aa))N(R^(cc))₂, —SO₂N(R^(c))₂, —SO₂R^(cc),—SO₂OR^(c), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(aa), —C(═S)SR^(c),C₁₋₁₀ alkyl (e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc) and R^(dd) are as defined herein. Aminoprotecting groups are well known in the art and include those describedin detail in Protecting Groups in Organic Synthesis, T. W. Greene and P.G. M. Wuts, ^(3rd) edition, John Wiley & Sons, 1999, incorporated hereinby reference.

For example, amino protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxycarbonylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Amino protecting groups such as carbamate groups (e.g., —C(═O)OR^(aa))include, but are not limited to, methyl carbamate, ethyl carbamante,9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Amino protecting groups such as sulfonamide groups (e.g., —S(═O)₂R^(aa))include, but are not limited to, p-toluenesulfonamide (Ts),benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), 3-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other amino protecting groups include, but are not limited to,phenothiazinyl-(10)-carbonyl derivative,N′-p-toluenesulfonylaminocarbonyl derivative, N′-phenylaminothiocarbonylderivative, N-benzoylphenylalanyl derivative, N-acetylmethioninederivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide,N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct (STABASE), 5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copperchelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on the oxygen atom is an“oxygen protecting group”. Oxygen protecting groups include, but are notlimited to —R—, —N(R^(bb))₂, —C(═O)R^(aa), —C(═O)OR^(aa), —C(═O)SR^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, the entirety of which isincorporated herein by reference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, a-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethylcarbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate(Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc),isobutyl carbonate, vinyl carbonate, allyl carbonate, p-nitrophenylcarbonate, benzyl carbonate, p-methoxybenzyl carbonate,3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzylcarbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate,methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxycarbonyl)benzoate, α-naphthoate,N,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate,dimethylphosphinothioyl, 2,4-dinitrophenylsulfenate, sulfate,methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). Forprotecting 1,2- or 1,3-diols, the protecting groups include methyleneacetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylideneketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylideneacetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal,cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal,2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal,2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethyleneacetal, dimethoxymethylene ortho ester, 1-methoxyethylidene ortho ester,1-ethoxyethylidine ortho ester, 1,2-dimethoxyethylidene ortho ester,α-methoxybenzylidene ortho ester, 1-(N,N-dimethylamino)ethylidenederivative, α-(N,N′-dimethylamino)benzylidene derivative,2-oxacyclopentylidene ortho ester, di-t-butylsilylene group (DTBS),1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS),tetra-t-butoxydisiloxane-1,3-diylidene derivative (TBDS), cycliccarbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

In certain embodiments, the substituent present on an sulfur atom is ansulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R, —Si(R^(aa))₃, —P(R^(aa))₂, —P(R^(aa))₃,—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(aa))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Sulfur protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

These and other exemplary substituents are described in more detail inthe Detailed Description, the Examples and in the Claims. The inventionis not intended to be limited in any manner by the above exemplarylisting of substituents.

As used herein, the terms “salt”, “acceptable salt”, or“pharmaceutically acceptable salt” refers to those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. For example, Berge et al., describespharmaceutically acceptable salts in detail in J. PharmaceuticalSciences (1977) 66:1-19. Pharmaceutically acceptable salts of thecompounds of this invention include those derived from suitableinorganic and organic acids and bases. Examples of pharmaceuticallyacceptable, nontoxic acid addition salts are salts of an amino groupformed with inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid and perchloric acid or with organic acidssuch as acetic acid, oxalic acid, maleic acid, tartaric acid, citricacid, succinic acid or malonic acid or by using other methods used inthe art such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N+(C₁₋₄alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

As used herein, the term “prodrug” means a compound that can hydrolyze,oxidize, or otherwise react under biological conditions (e.g., in vitroor in vivo enzymatic conditions) to provide a pharmacologically activecompound. In certain cases, a prodrug has improved physical and/ordelivery properties over the parent compound. Prodrugs are typicallydesigned to enhance pharmacologically, pharmaceutically and/orpharmacokinetically based properties associated with the parentcompound. The advantage of a prodrug can lie in its physical properties,such as enhanced water solubility for parenteral administration atphysiological pH compared to the parent compound, or it enhancesabsorption from the digestive tract, or it may enhance drug stabilityfor long-term storage.

Other Definitions

“Disease”, “disorder,” and “condition” are used interchangeably herein.

As used herein, an “individual” or “subject” to which administration iscontemplated includes, but is not limited to, humans (i.e., a male orfemale of any age group, e.g., a pediatric subject (e.g., child,adolescent) or adult subject (e.g., young adult, middle-aged adult orsenior adult)), other primates (e.g., cynomolgus monkeys, rhesusmonkeys) and commercially relevant mammals such as cattle, pigs, horses,sheep, goats, cats, and/or dogs. In any aspect and/or embodiment of theinvention, the mammal is a human.

As used herein, “local administration” or “administering locally” or“local effect” means administration/application of the active ingredientor active metabolite thereof directly, or in proximity to, a part of thebody, tissue, or lesion where said active substance is intended to exertits action. This may include, for example, topical administration to apart of the skin.

As used herein, unless otherwise specified, “topical administration” or“topically” means application to the surface of the skin, e.g., in anon-invasive manner.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” “an amount sufficient” or “sufficient amount” of acompound means the level, amount or concentration of the compound neededto treat a disease, disorder or condition, or to reduce or lower aparticular parameter (e.g., body fat) in the body of a subject, withoutcausing significant negative or adverse side effects to body or thetreated tissue. The term “therapeutically effective amount” canencompass an amount that improves overall therapy, reduces or avoidssymptoms or causes of disease or condition, or enhances the therapeuticefficacy of another therapeutically active agent.

As used herein, the terms “reduce”, “reduction”, “reducing”, “lower”, or“lowering” means to diminish or lessen the volume, size, mass, bulk,density, amount, and/or quantity of a substance (e.g., body fat, adiposetissue) in the body of a subject.

As used herein, the term “eliminate” means to completely remove anyunwanted or undesired volume, size, mass, bulk, density, amount, and/orquantity of a substance (e.g., excess body fat, excess adipose tissue)in the body of a subject.

As used herein, “suffer”, “suffers” or “suffering from” refers to asubject diagnosed with a particular disease or condition. As usedherein, “likely to suffer” refers to a subject who has not beendiagnosed with a particular disease or condition by a medicalpractitioner, but has a predisposition (e.g., genetic and/or physiologicpredisposition), or exhibits signs or symptoms of the disease orcondition.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease or condition, whichreduces the severity of the disease or condition, or retards or slowsthe progression of the disease or condition.

As used herein, unless otherwise specified, the terms “prevent,”“preventing” and “prevention” contemplate an action that occurs before asubject begins to suffer from the specified disease or condition, whichinhibits or reduces the severity of the disease or condition.

Conditions for which treatment and prevention are contemplated may befurther classified as a medical condition or a cosmetic condition. A“medical condition,” as used herein, refers to an abnormal conditionthat affects the body. A “cosmetic condition,” as used herein, refers toa condition other than a medical condition that affects the physicalappearance of the body. A cosmetic condition can occur, for example, dueto normal processes in a body, such as aging, pregnancy, puberty, andexposure to the sun or the elements, or due to normal features of abody, such as inherited facial features or body shapes that are found inhealthy individuals. Various medical and cosmetic conditions aredescribed herein. A “cosmetic method” refers to a method or procedureintended to ameliorate a cosmetic condition in the subject, e.g., forthe beautification of the subject's body or a part thereof, and a“cosmetic composition” is contemplated useful for such purpose. A“therapeutic method” refers to a method or procedure intended to treator prevent a medical condition, and a “pharmaceutical composition” iscontemplated useful for such purpose. However, while pharmaceuticalcompositions are contemplated useful for therapeutic and prophylacticpurposes, and cosmetic compositions are contemplated useful for cosmeticpurposes, there is overlap between the two compositions in terms of useof the composition. For example, a pharmaceutical composition is alsocontemplated useful for beautification purposes.

As used herein, unless otherwise specified, “excess submental fat” meansexcess fat on the body region including the mentum, the underside of thejaw, and the anterior neck, for example to the level of the inferiorborder of the cricoid.

As used herein, unless otherwise specified, “steatoblepharon” refers toa condition characterized by excess fat of the eyelids and/orperiorbital tissue. The excess fat can be due to prolapse of orbital orperiorbital fat. Steatoblepharon can occur in the lower or upper eyelid,or both. Steatoblepharon can be considered a cause of “eye bags.”

The presence, amount, or severity of excess fat can be assessedobjectively, e.g., by magnetic resonance imaging, computed tomography,biopsy, or skin calipers, or subjectively, e.g., by a clinician, apatient, or other observer, optionally with reference to a photonumeric,verbal, or descriptive scale or classification system, e.g., a five-stepseverity scale.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present invention relates to new stable, manufacturable,well-tolerated, aesthetically pleasing compositions that, when appliedto the skin, deliver a therapeutically effective amount of aprostaglandin FP receptor agonist (PFPRA compound), e.g., aprostaglandin F2α analog, e.g., latanoprost or tafluprost, tosubcutaneous fat. More specifically, the invention relates tocompositions for delivery of a PFPRA compound to subcutaneous fat,comprising a PFPRA compound and a fatty acid, e.g., oleic acid. Theformulations are useful for local reduction of subcutaneous fat, and forother therapeutic uses as described herein. The invention also relatesto methods for locally reducing body fat, comprising administering theinventive compositions to the skin.

As described herein, no theoretical framework was available to theinventors to select or improve a topical composition for delivering aPFPRA compound to subcutaneous fat. Rather, the inventors found itnecessary to test a wide range of conditions both in vitro and in vivo,with different formulation components at different concentrations and indifferent combinations. This testing led to the discovery that inclusionof oleic acid in the composition conferred exceptionally betterperformance for delivery of a PFPRA compound and reduction ofsubcutaneous fat compared to, for example, use of 1,3-butanediol,diethylene glycol monoethyl ether, dimethylsulfoxide, ethanol, glycerolmonooleate, hydroxypropyl cellulose, lauryl lactate, methyl laurate,oleyl alcohol, polysorbate 80, propylene glycol, and combinationsthereof.

Without wishing to be bound by any particular theory, the specialproperties conferred by combining oleic acid and a PFPRA may owe tocertain similarities between oleic acid and the PFPRA compound or activemetabolites thereof, i.e., similar structure and similar polarity. Forexample, the active metabolite of latanoprost, latanoprost free acid,and oleic acid are both carboxylic acids of similar structure andpolarity. As shown in FIG. 1, in their energy-minimized conformations,both compounds have a similar three-dimensional structure. Furthermore,according to this structural hypothesis, latanoprost free acid per secould serve as a penetration enhancer in this context, in that its 5-cisdouble bond (likewise present in most other PFPRA compounds) may improvethe penetration characteristics of oleic acid, as the structural kink ofunsaturated molecules is known to interfere with close packing of thephospholipid bilayer and can thereby improve penetration.

In some embodiments, the composition comprises a PRPRA compoundcarboxylic acid and a fatty acid, wherein both acids comprise the samealiphatic (—R^(FA1))tail. In some embodiments, the composition comprisesa PRPRA compound carboxylic acid and a fatty acid, wherein both acidscomprise aliphatic tails (R^(FA1)) of Similar chain length.

Furthermore, according to the above theory, the skilled artisan willappreciate that in certain embodiments, oleic acid can be substituted byone or more fatty acids of similar structure, e.g., wherein thealiphatic moiety of the fatty acid (R^(FA1)) is optionally substitutedC₁₀-C₂₀ alkyl or optionally substituted C₁₀-C₂₀ alkenyl.

In certain embodiments, R^(FA1) is an optionally substituted C₁₀-C₁₉alkyl, C₁₀-C₁₈ alkyl, C₁₀-C₁₇ alkyl, C₁₀-C₁₆ alkyl, C₁₀-C₁₅ alkyl,C₁₀-C₁₄ alkyl, C₁₀-C₁₃ alkyl, C₁-C₂₀ alkyl, C₁₁-C₁₉ alkyl, C₁-C₁₈ alkyl,C₁₁-C₁₇ alkyl, C₁-C₁₆ alkyl, C₁₁-C₁₅ alkyl, C₁-C₁₄ alkyl, C₁₁-C₁₃ alkyl,C₁₂-C₁₉ alkyl, C₁₂-C₁₈ alkyl, C₁₂-C₁₇ alkyl, C₁₂-C₁₆ alkyl, C₁₂-C₁₅alkyl, C₁₂-C₁₄ alkyl, C₁₂-C₁₃ alkyl, C₁₃-C₂₀ alkyl, C₁₃-C₁₉ alkyl,C₁₃-C₁₈ alkyl, C₁₃-C₁₇ alkyl, C₁₃-C₁₆ alkyl, C₁₃-C₁₅ alkyl, C₁₃-C₁₄alkyl, C₁₄-C₂₀ alkyl, C₁₄-C₁₉ alkyl, C₁₄-C₁₈ alkyl, C₁₄-C₁₇ alkyl,C₁₄-C₁₆ alkyl, C₁₄-C₁₅ alkyl, C₁₅-C₂₀ alkyl, C₁₅-C₁₉ alkyl, C₁₅-C₁₅alkyl, C₁₅-C₁₇ alkyl, or C₁₅-C₁₆ alkyl. In certain embodiments, R^(FA1)is a straight chain (unbranched) alkyl group. In certain embodiments,R^(FA1) is an unsubstituted alkyl group, i.e., comprising only carbonand hydrogen atoms. In certain embodiments, R^(FA1) is a substitutedalkyl group, e.g., substituted by halogen atoms.

In certain embodiments, R^(FA1) is an optionally substituted C₁₀-C₁₉alkenyl, C₁₀-C₁₈ alkenyl, C₁₀-C₁₇ alkenyl, C₁₀-C₁₆ alkenyl, C₁₀-C₁₅alkenyl, C₁₀-C₁₄ alkenyl, C₁₀-C₁₃ alkenyl, C₁-C₂₀ alkenyl, C₁₁-C₁₉alkenyl, C₁-C₁₈ alkenyl, C₁₁-C₁₇ alkenyl, C₁-C₁₆ alkenyl, C₁₁-C₁₅alkenyl, C₁-C₁₄ alkenyl, C₁-C₁₃ alkenyl, C₁₂-C₁₉ alkenyl, C₁₂-C₁₈alkenyl, C₁₂-C₁₇ alkenyl, C₁₂-C₁₆ alkenyl, C₁₂-C₁₅ alkenyl, C₁₂-C₁₄alkenyl, C₁₂-C₁₃ alkenyl, C₁₃-C₂₀ alkenyl, C₁₃-C₁₉ alkenyl, C₁₃-C₁₈alkenyl, C₁₃-C₁₇ alkenyl, C₁₃-C₁₆ alkenyl, C₁₃-C₁₅ alkenyl, C₁₃-C₁₄alkenyl, C₁₄-C₂₀ alkenyl, C₁₄-C₁₉ alkenyl, C₁₄-C₁₈ alkenyl, C₁₄-C₁₇alkenyl, C₁₄-C₁₆ alkenyl, C₁₄-C₁₅ alkenyl, C₁₅-C₂₀ alkenyl, C₁₅-C₁₉alkenyl, C₁₅-C₁₈ alkenyl, C₁₅-C₁₇ alkenyl, C₁₅-C₁₆ alkenyl. In certainembodiments, R^(FA1) is a unbranched alkenyl group. In certainembodiments, R^(FA1) is an unsubstituted alkenyl group, i.e., comprisingonly carbon and hydrogen atoms. In certain embodiments, R^(FA1) is asubstituted alkenyl group, e.g., substituted by halogen atoms. Incertain embodiments, R^(FA1) is an alkenyl group comprising 1, 2, 3, or4 double bonds, each independently cis or trans.

In certain embodiments, R^(FA1) is an alkenyl group comprising at leastone cis double bond, e.g., 1, 2, 3, or 4 cis double bonds. In certainembodiments, R^(FA1) is an alkenyl group of formula (a):

wherein:

p is an integer between 2 and 8, inclusive;

q is an integer between 1 and 8, inclusive; and

R^(FA2) is an optionally substituted C₁-C₁₀ alkyl, or an optionallysubstituted C₂-C₁₀alkenyl,

provided the sum of carbons of formula (a) does not exceed 20.

In certain embodiments, R^(FA2) is an optionally substituted C₁-C₉alkyl, C₁-C₈ alkyl, C₁-C₇ alkyl, C₁-C₆ alkyl, C₁-C₅ alkyl, C₁-C₄ alkyl,C₁-C₃ alkyl, C₁-C₂ alkyl, C₂-C₁₀ alkyl, C₂-C₉ alkyl, C₂-C₈ alkyl, C₂-C₇alkyl, C₂-C₆ alkyl, C₂-C₅ alkyl, C₂-C₄ alkyl, C₂-C₃ alkyl, C₃-C₁₀ alkyl,C₃-C₉ alkyl, C₃-C₈ alkyl, C₃-C₇ alkyl, C₃-C₆ alkyl, C₃-C₅ alkyl, C₃-C₄alkyl, C₄-C₁₀ alkyl, C₄-C₉ alkyl, C₄-C₈ alkyl, C₄-C₇ alkyl, C₄-C₆ alkyl,C₄-C₅ alkyl, C₅-C₁₀ alkyl, C₅-C₉ alkyl, C₅-C₅ alkyl, C₅-C₇ alkyl, C₅-C₆alkyl, C₆-C₁₀ alkyl, C₆-C₉ alkyl, C₆-C₈ alkyl, C₆-C₇ alkyl, C₇-C₁₀alkyl, C₇-C₉ alkyl, C₇-C₅ alkyl, C₅-C₁₀ alkyl, C₅-C₉ alkyl, or C₉-C₁₀alkyl. In certain embodiments, R^(FA2) is a straight chain (unbranched)alkyl group. In certain embodiments, R^(FA2) is an unsubstituted alkylgroup, i.e., comprising only carbon and hydrogen atoms. In certainembodiments, R^(FA2) is a substituted alkyl group, e.g., substituted byhalogen atoms.

In certain embodiments, R^(FA2) is an optionally substituted C₂-C₉alkenyl, C₂-C₈ alkenyl, C₂-C₇ alkenyl, C₂-C₆ alkenyl, C₂-C₅ alkenyl,C₂-C₄ alkenyl, C₂-C₃ alkenyl, C₃-C₁₀ alkenyl, C₃-C₉ alkenyl, C₃-C₈alkenyl, C₃-C₇ alkenyl, C₃-C₆ alkenyl, C₃-C₅ alkenyl, C₃-C₄ alkenyl,C₄-C₁₀ alkenyl, C₄-C₉ alkenyl, C₄-C₈ alkenyl, C₄-C₇ alkenyl, C₄-C₆alkenyl, C₄-C₅ alkenyl, C₅-C₁₀ alkenyl, C₅-C₉ alkenyl, C₅-C₈ alkenyl,C₅-C₇ alkenyl, C₅-C₆ alkenyl, C₆-C₁₀ alkenyl, C₆-C₉ alkenyl, C₆-C₈alkenyl, C₆-C₇ alkenyl, C₇-C₁₀ alkenyl, C₇-C₉ alkenyl, C₇-C₅ alkenyl,C₅-C₁₀ alkenyl, C₅-C₉ alkenyl, or C₉-C₁₀ alkenyl. In certainembodiments, R^(FA2) is a straight chain (unbranched) alkenyl group. Incertain embodiments, R^(FA2) is an unsubstituted alkenyl group, i.e.,comprising only carbon and hydrogen atoms. In certain embodiments,R^(FA2) is a substituted alkenyl group, e.g., substituted by halogenatoms. In certain embodiments, R^(FA2) is a substituted alkenyl group,e.g., substituted by halogen atoms. In certain embodiments, R^(FA2) isan alkenyl group comprising 1 or 2 double bonds, each independently cisor trans.

In certain embodiments, p is 2, 3, 4, 5, 6, 7, or 8. In certainembodiments, q is 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, pis 4, 5, 6, or 7. In certain embodiments, q is 1. In certainembodiments, q is 3, 4, or 5. In certain embodiments, q is 6, 7, or 8.

In certain embodiments, R^(FA1) is selected from any one of thefollowing saturated or unsaturated fatty acyl moieties:

Lauric —(CH₂)₁₀CH₃ (11 aliphatic carbons),Myristic —(CH₂)₁₂CH₃ (13 aliphatic carbons),Palmitic —(CH₂)₁₄CH₃ (15 aliphatic carbons),Stearic —(CH₂)₁₆CH₃ (17 aliphatic carbons),Myristoleic —(CH₂)₇CH═CH(CH₂)₃CH₃, i.e., of formula

wherein p=7, q=3, R^(FA2)═—CH₃ (13 aliphatic carbons)Palmitoleic* —(CH₂)₇CH═CH(CH₂)₅CH₃, i.e., of formula

wherein p=7, q=5, R^(FA2)═—CH₃ (15 aliphatic carbons)Sapienic* —(CH₂)₄CH═CH(CH₂)₈CH₃, i.e., of formula

wherein p=4, q=8, R^(FA2)═—CH₃ (15 aliphatic carbons)Oleic —(CH₂)₇CH═CH(CH₂)₇CH₃, i.e., of formula

wherein p=7, q=7, R^(FA2)═—CH₃ (17 aliphatic carbons)Linoleic* —(CH₂)₇CH═CH CH═CH(CH₂)₄CH₃, i.e., of formula

wherein p=7, q=1, R^(FA2) C₇-alkenyl (17 aliphatic carbons)α-Linolenic** —(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃, i.e., of formula

wherein p=7, q=1, R^(FA2) ═C₇-alkenyl (17 aliphatic carbons)

In certain embodiments, the total number of aliphatic carbons atoms inthe fatty acid is between 11 and 19, inclusive, i.e., 11, 12, 13, 14,15, 16, 17, 18, or 19 aliphatic carbon atoms total.

In certain embodiments, the total number of aliphatic carbons in thefatty acid is selected to approximate the aliphatic chain length of thePFPRA compound (e.g., latanoprost has 13 aliphatic carbons if thecyclizing carbons 9 through 11 of the cyclopentyl ring are not counted).

For example, in certain embodiments, the PFPRA compound has between 11and 19 total carbon atoms in the aliphatic chain of the PFPRA compound,i.e., 11, 12, 13, 14, 15, 16, 17, 18, or 19 aliphatic carbon atomstotal.

In some embodiments, fatty acid is selected such that its predictedlength (e.g., by molecular modeling) is similar (e.g., within ±3 Å) tothe predicted length of the PFPRA compound. For example, oleic acid hasa predicted length (between the two most distant heavy atoms) of about19 Å, which compares favorably with a length of about 17 Å forlatanoprost free acid, tafluprost free acid, and bimatoprost free acid;18 Å for latanoprost and tafluprost; about 19 Å for bimatoprost andtravoprost free acid (i.e., fluprostenol), and about 20 Å fortravoprost. In some embodiments, the predicted length is in anenergy-minimized conformation. In some embodiments, the predicted lengthis of a conformation whereby freely rotating bonds are rotated as toprovide a maximal length.

In some embodiments, the composition further comprises one or moreorganic alcohols, e.g., ethanol, propylene glycol, methanol, propanol,isopropanol, 1,3-butanediol, or ethylene glycol. In certain embodiments,the organic alcohol is propylene glycol and/or ethanol. However, incertain embodiments, 1,3-butanediol is excluded.

PFPRA Compounds

As used herein, a “PFPRA compound” can be any therapeutically relevant,naturally occurring or synthetic prostaglandin or prostaglandin analog,provided that it or its active metabolite (e.g., if an ester, the parentacid) suitably agonizes a prostaglandin FP receptor in a suitablefunctional assay. As used herein, a suitable degree of agonism can bedefined, for example, as a half maximal effective concentration (EC₅₀)of 1 micromolar or less, preferably 100 nanomolar or less. A suitablefunctional assay can be, for example, assessment of phosphoinositideturnover in HEK293 cells expressing a cloned FP prostaglandin receptor.See, e.g., Sharif et al., J. Ocular Pharmacol. Ther. 2002; 18:313-324.Many PFPRA compounds can be classified as prostaglandins, prostanoids,or prostamides. Naturally occurring prostaglandins are a class ofstructurally related eicosanoid hormones that are derived enzymaticallyfrom arachidonic acid. An example of a naturally occurring prostaglandinPFPRA compound is prostaglandin F2c. Exemplary synthetic prostaglandins,which are prostaglandin F2c analogs, include, but are not limited to,latanoprost, latanoprost free acid, bimatoprost, bimatoprost free acid,tafluprost, tafluprost free acid, travoprost, travoprost free acid(a.k.a. fluprostenol), and prodrugs (e.g., 9-, 11-, and/or 15-esterderivatives) thereof.

In certain embodiments, the PFPRA compound is a compound of Formula (I)or (II):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof;wherein:

L is a group of the formula

each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration;

A is optionally substituted C₁₋₁₀alkylene, optionally substitutedC₂₋₁₀alkenylene, or optionally substituted C₂₋₁₀ alkynylene, wherein thealkylene, alkenylene, or alkynylene group is optionally interrupted byone or more —O— or —S— groups;

B is hydrogen, optionally substituted C₃₋₇carbocyclyl, optionallysubstituted 3-8-membered-heterocyclyl, optionally substituted5-14-membered-heteroaryl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₁₋₃₀alkyl, optionally substituted C₂₋₃₀alkenyl, oroptionally substituted C₂₋₃₀alkynyl;

X is —OR₄, —SR₄, or —N(R₄)₂, wherein each instance of R₄ isindependently hydrogen, optionally substituted C₁₋₃₀alkyl, optionallysubstituted C₂₋₃₀alkenyl, optionally substituted C₂₋₃₀alkynyl, —C(═O)R₅,or —C(═O)OR₅, wherein R₅ is optionally substituted C₁₋₃₀alkyl,optionally substituted C₂₋₃₀alkenyl, or optionally substitutedC₂₋₃₀alkynyl, or two R₄ groups are joined to form an optionallysubstituted 3-8-membered-heterocyclyl or optionally substituted5-14-membered-heteroaryl ring;

Z is ═O, ═S, or ═NR_(Z), wherein R_(Z) is selected from hydrogen, anamino protecting group, —OH, substituted hydroxyl, optionallysubstituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇carbocyclyl,optionally substituted 3-8-membered-heterocyclyl, optionally substitutedC₆₋₁₀aryl, or optionally substituted 5-14-membered-heteroaryl, or Zrepresents two hydrogen atoms; with regard to the compound of Formula(I), one of R₁ and R₂ is ═O, —OH, or a —O(CO)R₆ group and the other oneis —OH or —O(CO)R₆, or R₁ is ═O and R₂ is H, wherein R₆ is an optionallysubstituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl, optionallysubstituted C₂₋₂₀ alkynyl, or —(CH₂)_(m)R₇ wherein m is 0 or an integerof between 1-10, inclusive, and R₇ is optionally substitutedC₃₋₇carbocyclyl, optionally substituted 3-8-membered-heterocyclyl,optionally substituted C₆₋₁₀aryl, or optionally substituted5-14-membered-heteroaryl; and

with regard to the compound of Formula (I), R₁ is ═O, —OH, or —O(CO)R₆,wherein R₆ is a an optionally substituted C₁₋₂₀alkyl, optionallysubstituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, or—(CH₂)_(m)R₇ wherein m is 0 or an integer of between 1-10, inclusive,and R₇ is optionally substituted C₃₋₇carbocyclyl, optionally substituted3-8-membered-heterocyclyl, optionally substituted C₆₋₁₀aryl, oroptionally substituted 5-14-membered-heteroaryl.

In certain embodiments, the endocyclic dotted lines of Formula (I)(i.e., depicted in the 5-membered ring) each represent a single bond.

For example, in certain embodiments, wherein the endocyclic dotted linesof Formula (I) each represent a single bond, provided is a compoundhaving any one of the following stereochemistry:

pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof, wherein

, R₁, R₂, A, B, Z and X are as defined herein.

In certain embodiments, the exocyclic dotted line

(i.e. depicted outside of the 5-membered ring) of Formula (I) or (II) ora subset thereof represents a double bond in the cis or transconfiguration. In certain embodiments, the exocyclic dotted line

represents a double bond in the cis configuration.

In certain embodiments, each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration.

As generally defined above, one of R₁ and R₂ is ═O, —OH, or a —O(CO)R₆group and the other one is —OH or —O(CO)R₆, or R₁ is ═O and R₂ is H,wherein R₆ is an optionally substituted C₁₋₂₀ alkyl, optionallysubstituted C₂₋₂₀ alkenyl, optionally substituted C₂₋₂₀ alkynyl, or—(CH₂)_(m)R₇ wherein m is 0 or an integer of between 1-10, inclusive,and R is optionally substituted C₃₋₇carbocyclyl, optionally substituted3-8-membered-heterocyclyl, optionally substituted C₆₋₁₀aryl, oroptionally substituted 5-14-membered-heteroaryl.

In certain embodiments, R₁ is ═O and R₂ is H.

In certain embodiments, one of R₁ and R₂ is —OH, substituted hydroxyl,or —O(CO)R₆, and the other one is —OH, substituted hydroxyl, or—O(CO)R₆.

In certain embodiments, both R₁ and R₂ are —OH.

In certain embodiments, one of R₁ and R₂ is —OH, and the other one is—O(CO)R₆. In certain embodiments, R₁ is —OH, and R₂ is —O(CO)R₆. Incertain embodiments, R₂ is —OH, and R₁ is —O(CO)R₆. In certainembodiments, R₆ is an optionally substituted C₁₋₂₀alkyl, e.g.,optionally substituted C₁₋₅alkyl, optionally substituted C₁₋₁₀alkyl,optionally substituted C₁₋₈alkyl, optionally substituted C₁₋₆alkyl,optionally substituted C₁₋₅alkyl, optionally substituted C₁₋₄alkyl,optionally substituted C₁₋₃alkyl, or optionally substituted C₁₋₂alkyl.In certain embodiments, R₆ is —(CH₂)_(r)CH₃ wherein r is 0, 1, 2, 3, 4,5, or 6, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃.

As generally defined above, A is optionally substituted C₁₋₁₀alkylene,optionally substituted C₂₋₁₀alkenylene or optionally substitutedC₂₋₁₀alkynylene, wherein the alkylene, alkenylene, or alkynylene groupis optionally interrupted by one or more —O— or —S— groups.

In certain embodiments, A is optionally substituted C₁₋₁₀alkylene,optionally substituted C₂₋₁₀alkenylene or optionally substitutedC₂₋₁₀alkynylene, wherein the alkylene, alkenylene, or alkynylene groupis optionally interrupted by one —O— group.

In certain embodiments, A is optionally substituted C₄₋₆alkylene,optionally substituted C₄₋₆alkenylene or optionally substitutedC₄₋₆alkynylene, wherein the alkylene, alkenylene, or alkynylene group isoptionally interrupted by one —O— group.

In certain embodiments, A is optionally substituted C₄₋₆alkyleneoptionally interrupted by one —O— group. In certain embodiments, A isoptionally substituted C₄₋₆alkenylene optionally interrupted by one —O—group. In certain embodiments, A is optionally substitutedC₄₋₆alkynylene optionally interrupted by one —O— group.

In certain embodiments, A is substituted with one or more groupsselected from the group consisting of halogen, —OH, substitutedhydroxyl, or —O(CO)R₈, wherein R₈ is optionally substituted C₁₋₂₀alkyl,optionally substituted C₂₋₂₀alkenyl, optionally substitutedC₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 or an integer between 1-10,inclusive, and R₉ is optionally substituted C₃₋₇carbocyclyl, optionallysubstituted C₆₋₁₀aryl, and optionally substituted5-14-membered-heteroaryl.

In certain embodiments, A is substituted with ═O.

In certain embodiments, A is substituted with —OC(═O)R₈, wherein R₈ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉, wherein m is 0 oran integer between 1-10, inclusive, and R₉ is optionally substitutedC₃₋₇carbocyclyl, optionally substituted C₆₋₁₀aryl, or optionallysubstituted 5-14-membered-heteroaryl.

In certain embodiments, A is substituted with —OH or substitutedhydroxyl.

In certain embodiments, A is substituted with substituted hydroxyl.

In certain embodiments, A is substituted with —OH.

In certain embodiments, A is a group of the Formula (i), (ii), (iii),(iv), (v), or (vi):

wherein each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration;

each instance of R₃ and R₃′ is hydrogen, halogen, —OH, substitutedhydroxyl, or —O(CO)R₈, wherein R₈ is optionally substituted C₁₋₂₀alkyl,optionally substituted C₂₋₂₀alkenyl, optionally substitutedC₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 or an integer between 1-10,inclusive, and R₉ is optionally substituted C₃₋₇carbocyclyl, optionallysubstituted C₆₋₁₀aryl, or optionally substituted5-14-membered-heteroaryl, or R₃ and R₃′ are joined to form ═O;

G is —O— or —S—;

y is 0, 1, or 2; and

x is 0 or 1.

In certain embodiments, G is —O—. In certain embodiments, G is —S—.

In certain embodiments,

of Formula (i), (ii), or (iii) represents a double bond in the cisconfiguration.

In certain embodiments,

of Formula (i), (ii), or (iii) represents a double bond in the transconfiguration.

In certain embodiments, the group of the Formula (i) is of the formula:

In certain embodiments, the group of the Formula (ii) is of the formula:

In certain embodiments,

of Formula (i), (ii), or (iii) represents a single bond.

In certain embodiments, the group of the Formula (i) is of the formula:

In certain embodiments, the group of the Formula (ii) is of the formula:

As generally defined above, each instance of R₃ and R₃′ is independentlyhydrogen, halogen, —OH, substituted hydroxyl, or —O(CO)R₈, wherein R₈ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 oran integer between 1-10, inclusive, and R₉ is optionally substitutedC₃₋₇carbocyclyl, optionally substituted C₆₋₁₀aryl, or optionallysubstituted 5-14-membered-heteroaryl; or R₃ and R₃′ are joined to form═O.

In certain embodiments, R₃ is hydrogen. In certain embodiments, R₃′ ishydrogen. In certain embodiments, R₃ is hydrogen and R₃′ is anon-hydrogen group. In certain embodiments, R₃′ is hydrogen and R₃ is anon-hydrogen group. In certain embodiments, however, neither R₃ nor R₃′is hydrogen.

In certain embodiments, R₃ and R₃′ are joined to form ═O.

In certain embodiments, R₃ and R₃′ are the same group. In certainembodiments, R₃ and R₃′ are different groups.

In certain embodiments, R₃ is —OH, substituted hydroxyl, or —O(CO)R₈,wherein R₈ is optionally substituted C₁₋₂₀alkyl, optionally substitutedC₂₋₂₀alkenyl, optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉wherein m is 0 or an integer between 1-10, inclusive, and R₉ isoptionally substituted C₃₋₇carbocyclyl, optionally substitutedC₆₋₁₀aryl, or optionally substituted 5-14-membered-heteroaryl. Incertain embodiments, R₃ is —O(CO)R₈. In certain embodiments, R₃ is—O(CO)R₈, and R₈ is optionally substituted C₁₋₂₀alkyl, e.g., optionallysubstituted C₁₋₁₅alkyl, optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₁₋₈alkyl, optionally substituted C₁₋₆alkyl, optionallysubstituted C₁₋₅alkyl, optionally substituted C₁₋₄alkyl, optionallysubstituted C₁₋₃alkyl, or optionally substituted C₁₋₂alkyl. In certainembodiments, R₃ is —O(CO)R₈, and R₈ is —(CH₂)_(g)CH₃ wherein q is 0, 1,2, 3, 4, 5, or 6, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃. Incertain embodiments, R₃ is —OH or substituted hydroxyl. In certainembodiments, R₃ is substituted hydroxyl. In certain embodiments, R₃ is—OH.

In certain embodiments, R₃′ is —OH, substituted hydroxyl, or —O(CO)R₈,wherein R₈ is optionally substituted C₁₋₂₀alkyl, optionally substitutedC₂₋₂₀alkenyl, optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉wherein m is 0 or an integer between 1-10, inclusive, and R₉ isoptionally substituted C₃₋₇carbocyclyl, optionally substitutedC₆₋₁₀aryl, or optionally substituted 5-14-membered-heteroaryl. Incertain embodiments, R₃′ is —O(CO)R₈. In certain embodiments, R₃′ is—O(CO)R₈, and R₈ is optionally substituted C₁₋₂₀alkyl, e.g., optionallysubstituted C₁₋₁₅alkyl, optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₁₋₈alkyl, optionally substituted C₁₋₆alkyl, optionallysubstituted C₁₋₅alkyl, optionally substituted C₁₋₄alkyl, optionallysubstituted C₁₋₃alkyl, or optionally substituted C₁₋₂alkyl. In certainembodiments, R₃′ is —O(CO)R₈, and R₈ is —(CH₂)_(g)CH₃ wherein q is 0, 1,2, 3, 4, 5, or 6, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃. Incertain embodiments, R₃′ is —OH or substituted hydroxyl. In certainembodiments, R₃′ is substituted hydroxyl. In certain embodiments, R₃′ is—OH.

In certain embodiments, R₃ is halogen, e.g., selected from fluoro,chloro, bromo, and iodo. In certain embodiments, R₃′ is halogen, e.g.,selected from fluoro, chloro, bromo, and iodo. In certain embodiments,R₃ is halogen and R₃′ is halogen, e.g., each independently selected fromfluoro, chloro, bromo, and iodo. In certain embodiments, both R₃ and R₃′are fluoro.

In certain embodiments, y is 0; and x is 1. In certain embodiments, y is0; and x is 0. In certain embodiments, y is 1; and x is 1. In certainembodiments, y is 1; and x is 0. In certain embodiments, y is 2; and xis 0. In certain embodiments, y is 2; and x is 1.

As defined generally above, B is hydrogen, optionally substitutedC₃₋₇carbocyclyl, optionally substituted 3-8-membered-heterocyclyl,optionally substituted 5-14-membered-heteroaryl, optionally substitutedC₆₋₁₀aryl, optionally substituted C₁₋₃₀alkyl, optionally substitutedC₂₋₃₀alkenyl, or optionally substituted C₂₋₃₀alkynyl.

In certain embodiments, B is hydrogen.

In certain embodiments, B is optionally substituted C₁₋₃₀alkyl. Incertain embodiments, B is optionally substituted C₂₋₃₀alkenyl. Incertain embodiments, B is optionally substituted C₂₋₃₀alkynyl.

In certain embodiments, B is optionally substituted C₃₋₇carbocyclyl,e.g., optionally substituted cyclohexyl. In certain embodiments, B isoptionally substituted 3-8-membered-heterocyclyl. In certainembodiments, B is optionally substituted 5-14-membered-heteroaryl. Incertain embodiments, B is optionally substituted C₆₋₁₀aryl. In certainembodiments, B is optionally substituted C₁₀aryl (i.e., phenyl). Incertain embodiments, B is optionally substituted C₁₀aryl (i.e.,napthyl).

For example, in certain embodiments, B is an optionally substitutedphenyl of the Formula (viii):

wherein:

Y is selected from the group consisting of optionally substitutedC₁₋₁₀alkyl, C₁₋₁₀perhaloalkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, halo, nitro, cyano, thiol,substituted thiol, hydroxyl, substituted hydroxyl, amino,monosubstituted amino, and disubstituted amino; and n is 0 or an integerof from 1 to 5, inclusive.

In certain embodiments, n is 0 or an integer from 1 to 3, inclusive. Incertain embodiments, n is 0 or an integer from 1 to 2, inclusive. Incertain embodiments, n is 0. In certain embodiments, n is 1. In certainembodiments, n is 2. In certain embodiments, n is 3.

For example, in certain embodiments, wherein n is 1, the group of theFormula (viii) is of the formula:

In certain embodiments, wherein n is 2, the group of the Formula (viii)is of the formula:

In certain embodiments, Y is halo, i.e. selected from fluoro, iodo,bromo, or chloro. In certain embodiments Y is chloro. In certainembodiments Y is fluoro.

In certain embodiments, Y is optionally substituted C₁₋₁₀alkyl orC₁₋₁₀perhaloalkyl.

In certain embodiments, Y is optionally substituted C₁₋₁₀alkyl. Incertain embodiments, Y is optionally substituted C₁₋₆alkyl. In certainembodiments, Y is optionally substituted C₁₋₄alkyl. In certainembodiments, Y is optionally substituted C₁₋₃alkyl. In certainembodiments, Y is optionally substituted C₁₋₂alkyl. In certainembodiments, Y is —CH₃, —CH₂F, or —CHF₂.

In certain embodiments, Y is C₁₋₁₀perhaloalkyl. In certain embodiments,Y is C₁₋₆perhaloalkyl. In certain embodiments, Y is C₁₋₄perhaloalkyl. Incertain embodiments, Y is C₁₋₃perhaloalkyl. In certain embodiments, Y isC₁₋₂perhaloalkyl. In certain embodiments, Y is —CF₃, —CF₂Cl, or —CFCl₂.

As generally defined above, Z is ═O, ═S, or ═NR_(Z), wherein R_(Z) isselected from hydrogen, an amino protecting group, —OH, substitutedhydroxyl, optionally substituted C₁₋₁₀alkyl, optionally substitutedC₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl, optionallysubstituted C₃₋₇carbocyclyl, optionally substituted3-8-membered-heterocyclyl, optionally substituted C₆₋₁₀aryl, oroptionally substituted 5-14-membered-heteroaryl, or Z represents twohydrogen atoms.

In certain embodiments, Z is ═O.

In certain embodiments, Z is ═S.

In certain embodiments, Z is ═NR_(Z), wherein R_(Z) is selected fromhydrogen, an amino protecting group, —OH, substituted hydroxyl,optionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, optionally substitutedC₃₋₇carbocyclyl, optionally substituted 3-8-membered-heterocyclyl,optionally substituted C₆₋₁₀aryl, or optionally substituted5-14-membered-heteroaryl. In certain embodiments, Z is ═NR_(Z) and R_(Z)is hydrogen.

In certain embodiments, Z represents two hydrogen atoms.

As generally defined above, X is —OR₄, —SR₄, or —N(R₄)₂, wherein eachinstance of R₄ is independently hydrogen, optionally substitutedC₁₋₃₀alkyl, optionally substituted C₂₋₃₀alkenyl, optionally substitutedC₂₋₃₀alkynyl, —C(═O)R₅, or —C(═O)OR₅, wherein R₅ is optionallysubstituted C₁₋₃₀alkyl, optionally substituted C₂₋₃₀alkenyl, oroptionally substituted C₂₋₃₀alkynyl, or two R₄ groups are joined to forman optionally substituted 3-8-membered-heterocyclyl or optionallysubstituted 5-14-membered-heteroaryl ring.

In certain embodiments, X is —OR₄. In certain embodiments, X is —OR₄,and R₄ is hydrogen. In certain embodiments, X is —OR₄, and R₄ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₄ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₄ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₄ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₄ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —OR₄, wherein R₄ is —C(═O)R₅, or —C(═O)OR₅.

In certain embodiments, X is —OR₄, and R₄ is —C(═O)R₅, and R₅ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀ alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₅ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —OR₄, and R₄ is —C(═O)OR₅ and R₅ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₅ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —SR₄. In certain embodiments, X is —SR₄,and R₄ is hydrogen. In certain embodiments, X is —SR₄, and R₄ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₄ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₄ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₄ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₄ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —SR₄, wherein R₄ is —C(═O)R₅, or —C(═O)OR₅.

In certain embodiments, X is —SR₄, and R₄ is —C(═O)R₅, and R₅ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₅ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —SR₄, and R₄ is —C(═O)OR₅ and R₅ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀ alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₆alkyl, e.g., C₁_3alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₅ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —N(R₄)₂. In certain embodiments, X is—N(R₄)₂ and at least one R₄ group is hydrogen. In certain embodiments, Xis —N(R₄)₂ and neither of the two R₄ groups are hydrogen. In certainembodiments, X is —N(R₄)₂ and at least one R₄ is optionally substitutedC₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl, or optionallysubstituted C₂₋₂₀alkynyl. In certain embodiments, X is —N(R₄)₂ and atleast one R₄ is optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₂₋₁₀alkenyl, or optionally substituted C₂₋₁₀alkynyl. Incertain embodiments, X is —N(R₄)₂ and at least one R₄ is optionallysubstituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, or C₄₋₆alkyl Incertain embodiments, X is —N(R₄)₂ and at least one R₄ is optionallysubstituted C₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl.In certain embodiments, X is —N(R₄)₂ and at least one R₄ is optionallysubstituted C₂₋₆alkynyl, e.g., C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.However, in certain embodiments, X is not —NH(iPr).

In certain embodiments, X is —N(R₄)₂ and at least one R₄ is —C(═O)R₅, or—C(═O)OR₅.

In certain embodiments, X is —N(R₄)₂ and at least one R₄ is —C(═O)R₅,and R₅ is optionally substituted C₁₋₂₀alkyl, optionally substitutedC₂₋₂₀alkenyl, or optionally substituted C₂₋₂₀alkynyl. In certainembodiments, R₅ is optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₂₋₁₀alkenyl, or optionally substituted C₂₋₁₀alkynyl. Incertain embodiments, R₅ is optionally substituted C₁₋₆alkyl, e.g.,C₁₋₃alkyl, C₃₋₄alkyl, or C₄₋₆alkyl. In certain embodiments, R₅ isoptionally substituted C₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, orC₄₋₆alkenyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkynyl, e.g., C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —N(R₄)₂ and at least one R₄ is —C(═O)OR₅and R₅ is optionally substituted C₁₋₂₀alkyl, optionally substitutedC₂₋₂₀alkenyl, or optionally substituted C₂₋₂₀alkynyl. In certainembodiments, R₅ is optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₂₋₁₀alkenyl, or optionally substituted C₂₋₁₀alkynyl. Incertain embodiments, R₅ is optionally substituted C₁₋₆alkyl, e.g.,C₁₋₃alkyl, C₃₋₄alkyl, or C₄₋₆alkyl. In certain embodiments, R₅ isoptionally substituted C₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, orC₄₋₆alkenyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkynyl, e.g., C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In other embodiments, X is —N(R₄)₂ and the two R₄ groups are joined toform an optionally substituted 3-8-membered-heterocyclyl or optionallysubstituted 5-14-membered-heteroaryl ring.

In certain embodiments, wherein X is —OR₄, —SR₄, or —N(R₄)₂, any one ofR₄ or R₅ is optionally substituted C₁₋₃₀alkyl (e.g., C₁₋₁₀alkyl,C₁₋₆alkyl, C₁₋₃alkyl, C₇₋₃₀alkyl, C₁₀₋₃₀alkyl, C₇₋₂₅alkyl, C₁₀₋₂₅alkyl,C₁₅₋₂₅alkyl). In certain embodiments, any one of R₄ or R₅ is optionallysubstituted C₂₋₃₀alkenyl (e.g., C₂₋₁₀alkenyl, C₂₋₆alkenyl, C₁₋₃alkenyl,C₇₋₃₀alkenyl, C₁₀₋₃₀alkenyl, C₇₋₂₅alkenyl, C₁₀₋₂₅alkenyl,C₁₅₋₂₅alkenyl). In certain embodiments, any one of R₄ or R₅ isoptionally substituted C₂₋₃₀alkynyl (e.g., C₂₋₁₀alkynyl, C₂₋₆alkynyl,C₁₋₃alkynyl, C₇₋₃₀alkynyl, C₁₀₋₃₀alkynyl, C₇₋₂₅alkynyl, C₁₀₋₂₅alkynyl,C₁₅₋₂₅alkynyl).

In any of the above embodiments, when R₄ or R₅ are defined as aC₇₋₃₀alkyl or C₇₋₃₀alkenyl groups, such groups may also be referred toas “lipid tails.” Lipid tails present in these lipid groups can besaturated and unsaturated, depending on whether or not the lipid tailcomprises double bonds. The lipid tail can also comprise differentlengths, often categorized as medium (i.e., with tails between 7-12carbons, e.g., C₇₋₁₂ alkyl or C₇₋₁₂ alkenyl), long (i.e., with tailsgreater than 12 carbons and up to 22 carbons, e.g., C₁₃₋₂₂ alkyl orC₁₃₋₂₂ alkenyl), or very long (i.e., with tails greater than 22 carbons,e.g., C₂₃-30 alkyl or C₂₃₋₃₀ alkenyl).

Exemplary unsaturated lipid tails include, but are not limited to:

Myristoleic —(CH₂)₇CH═CH(CH₂)₃CH₃,Palmitoliec —(CH₂)₇CH═CH(CH₂)₅CH₃,Sapienic —(CH₂)₄CH═CH(CH₂)₈CH₃,Oleic —(CH₂)₇CH═CH(CH₂)₇CH₃,Linoleic —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃,α-Linolenic —(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃,Arachinodonic —(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃,Eicosapentaenoic —(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃,Erucic —(CH₂)₁₁CH═CH(CH₂)₇CH₃, andDocosahexaenoic—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH—CH₂CH₃.

Exemplary saturated lipid tails include, but are not limited to:

-   -   Lauric —(CH₂)₁₀CH₃,    -   Myristic —(CH₂)₁₂CH₃,    -   Palmitic —(CH₂)₁₄CH₃,    -   Stearic —(CH₂)₁₆CH₃,    -   Arachidic —(CH₂)₁₈CH₃,    -   Behenic —(CH₂)₂OCH₃,    -   Lignoceric —(CH₂)₂₂CH₃, and    -   Cerotic —(CH₂)₂₄CH₃.

In certain embodiments of Formula (I), the compound is of Formula (I-a):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein;

each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration;

each instance of R₃ and R₃′ is independently hydrogen, halogen, —OH,substituted hydroxyl, or —O(CO)R₈, wherein R₈ is optionally substitutedC₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substitutedC₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 or an integer between 1-10,inclusive, and R₉ is optionally substituted C₃₋₇carbocyclyl, optionallysubstituted C₆₋₁₀aryl, or optionally substituted5-14-membered-heteroaryl, or R₃ and R₃′ are joined to form ═O;

Y is selected from the group consisting of optionally substitutedC₁₋₁₀alkyl, C₁₋₁₀perhaloalkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, halo, nitro, cyano, thiol,substituted thiol, hydroxyl, substituted hydroxyl, amino,monosubstituted amino, and disubstituted amino;

G is —O— or —S—;

y is 0, 1, or 2;

x is 0 or 1; and

n is 0 or an integer of from 1 to 5, inclusive.

In certain embodiments of Formula (I-a), wherein R₃′ is hydrogen, thecompound is of Formula (I-b):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments of Formula (I-a), wherein R₃ is hydrogen, thecompound is of Formula (I-c):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments, G is —O—. In certain embodiments, G is —S—.

In certain embodiments of Formula (I-a), wherein G is —O—, provided is acompound of Formula (I-a1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-b), wherein G is —O—, the compoundis of Formula (I-b1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-c), wherein G is —O—, the compoundis of Formula (I-c1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-a), wherein G is —S—, provided is acompound of Formula (I-a2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein; wherein

, R₁, R₂, R₃, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-b), wherein G is —S—, the compoundis of Formula (I-b2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-c), wherein G is —S—, the compoundis of Formula (I-c2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments, the compound of Formula (I-a) has the followingstereochemistry, also referred to herein as a compound of Formula (I-d):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, Z, Y, G, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d), wherein R₃′ is hydrogen, thecompound is of Formula (I-e):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d), wherein R₃ is hydrogen, thecompound is of Formula (I-f):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′ Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments, G is —O—. In certain embodiments, G is —S—.

In certain embodiments of Formula (I-d), wherein G is —O—, the compoundis of Formula (I-d1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, Z, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-e), wherein G is —O—, the compoundis of Formula (I-e1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-f), wherein G is —O—, the compoundis of Formula (I-f1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d), wherein G is —S—, the compoundis of Formula (I-d2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, Z, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-e), wherein G is —S—, the compoundis of Formula (I-e2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-f), wherein G is —S—, the compoundis of Formula (I-f2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments, Z is ═O. In certain embodiments, each

represents a single bond. In certain embodiments, each endocyclic

represents a single bond. In certain embodiments at least one exocyclic

represents a cis-double bond. In certain embodiments, each instance ofR₁ and R₂ is —OH. In certain embodiments, each instance of R₁ and R₂ is—O(CO)R₆. In certain embodiments, one of R₁ and R₂ is —OH, and the otherone is —O(CO)R₆. In certain embodiments, one of R₃ and R₃′ is —O(CO)R₈,and the other is hydrogen. In certain embodiments, R₁ is —OH, R₂ is—O(CO)R₆, one of R₃ and R₃′ is —OH, and the other is hydrogen. Incertain embodiments, R₂ is —OH, R₁ is —O(CO)R₆, one of R₃ and R₃′ is—OH, and the other is hydrogen. In certain embodiments, each of R₁ andR₂ is —OH, and one of R₃ and R₃′ is —O(CO)R₈, and the other is hydrogen.In certain embodiments, each instance of R₁ and R₂ is —O(CO)R₆, and oneof R₃ and R₃′ is —O(CO)R₈, and the other is hydrogen. In certainembodiments, —O(CO)R₆ and —O(CO)R₈ attached to the compound are the samegroup. In certain embodiments, —O(CO)R₆ and —O(CO)R₈ attached to thecompound are different groups.

In certain embodiments of Formula (I-d), wherein Z is ═O, eachendocyclic

presents a single bond, and at least one exocyclic

represents a cis-double bond, provided is a compound of Formula (I-d3)having the following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, G, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-e), wherein Z is ═O, eachendocyclic

represents a single bond, and at least one exocyclic

represents a cis-double bond, provided is a compound of Formula (I-e3)having the following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, G, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-f), wherein Z is ═O, eachendocyclic

represents a single bond, and at least one exocyclic

represents a cis-double bond, provided is a compound of Formula (I-f3)having the following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, G, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d3), wherein R₁ is —OH and R₂ is—O(CO)R₆, or wherein R₂ is —OH and R₁ is —O(CO)R₆, or wherein both R₁and R₂ are —O(CO)R₆, provided is a compound of Formula (I-d4), (I-d5),and (I-d6) having the following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₆, R₃, R₃′, G, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d3), wherein R₃ is —O(CO)R₈ or R₃′is —O(CO)R₈, provided is a compound of Formula (I-d7) and (I-d8) havingthe following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, R₈, G, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d3), wherein R₁ and R₂ are each —OHand R₃ is —O(CO)R₈, or wherein R₁ and R₂ are each —OH and R₃′ is—O(CO)R₈, provided is a compound of Formula (I-d9) and (I-d0) having thefollowing stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₃, R₃′, R₈, G, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-e3), wherein R₁ is —OH and R₂ is—O(CO)R₆, or wherein R₂ is —OH and R₁ is —O(CO)R₆, or wherein both R₁and R₂ are —O(CO)R₆, and R₃′ is hydrogen and R₃ is —OH, provided is acompound of Formula (I-d11), (I-d12), and (I-d13) having the followingstereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₆, R₃, R₃′, G, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d8), wherein each of R₁ and R₂ are—O(CO)R₆ and R₃′ is hydrogen, provided is a compound of Formula (I-d14)having the following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₆, R₈, G, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d2), wherein Z is ═O, each instanceof R₁ and R₂ is —OH, and each

represents a single bond, provided is a compound of Formula (I-g):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein X, Y, R₃, R₃′, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d1), wherein each instance of R₁and R₂ is —OH, and Z is —O, provided is a compound of Formula (I-h):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₃, R₃′, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-h), wherein R₃′ is hydrogen,provided is a compound of Formula (I-i):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₃, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-i), wherein R₃ is —OH, provided isa compound of Formula (I-j):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-h), wherein R₃ is F and R₃′ is F,provided is a compound of Formula (I-k):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-i), wherein R₃ is —O(CO)R₈,provided is a compound of Formula (I-o):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₈, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I), the compound of Formula (I-1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein;

each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration;

each instance of R₃ and R₃′ is independently hydrogen, halogen, —OH,substituted hydroxyl, or —O(CO)R₈, wherein R₈ is optionally substitutedC₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substitutedC₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 or an integer between 1-10,inclusive, and R₉ is optionally substituted C₃₋₇carbocyclyl, optionallysubstituted C₆₋₁₀aryl, or optionally substituted5-14-membered-heteroaryl, or R₃ and R₃′ are joined to form ═O;

Y is selected from the group consisting of optionally substitutedC₁₋₁₀alkyl, C₁₋₁₀perhaloalkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, halo, nitro, cyano, thiol,substituted thiol, hydroxyl, substituted hydroxyl, amino,monosubstituted amino, and disubstituted amino;

G is —O— or —S—;

y is 0, 1, or 2;

x is 0 or 1; and

n is 0 or an integer of from 1 to 5, inclusive.

In certain embodiments of Formula (I-1), wherein Z is ═O, and R₁ and R₂are each —OH, provided is a compound of Formula (I-m):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein.

In certain embodiments of Formula (I-m), wherein R₃′ is hydrogen, y is 2and x is 0, provided is a compound of Formula (I-n):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein.

As generally defined above, in certain embodiments, provided is acompound of Formula (II):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof, wherein A, B, X, Z, L, and R₁ are as defined herein are asdefined herein.

In certain embodiments, L is a group of the formula

wherein

represents a single bond.

In certain embodiments, L is a group of the formula

wherein

represents a double bond which can be in the cis or trans configuration.In certain embodiments, the double bond is in the cis configuration. Incertain embodiments, the double bond is in the trans configuration

In certain embodiments, L is a group of the formula

wherein

represents a single bond.

In certain embodiments, L is a group of the formula

wherein

represents a double bond which can be in the cis or trans configuration.In certain embodiments, the double bond is in the cis configuration. Incertain embodiments, the double bond is in the trans configuration

In certain embodiments of Formula (II), the compound of Formula (II-a):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof, wherein

, R₁, Z, X, Y, G, R₃, R₃′, y, x, and n are as defined herein.

In certain embodiments of Formula (II-a), wherein R₃′ is hydrogen, thecompound is of Formula (II-b):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₃, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments of Formula (II-a), wherein R₃ is hydrogen, thecompound is of Formula (II-c):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments, G is —O—. In certain embodiments, G is —S—.

In certain embodiments of Formula (II-a), wherein G is —O—, provided isa compound of Formula (II-a1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments, Z is ═O.

In certain embodiments at least one exocyclic

represents a cis-double bond.

For example, in certain embodiments of Formula (II-a1), wherein Z is ═O,provided is a compound of Formula (II-d):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₃, R₃′, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (II-d), wherein R₁ is OH, R₃′ ishydrogen, R₃ is —OH, y is 0, and x is 1, provided is a compound ofFormula (II-e):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, Y, X, and n are as defined herein.

Exemplary compounds of Formula (I) include, but are not limited to:

referred to herein as Prostaglandin F2α;

also referred to herein as bimatoprost;

also referred to herein as bimatoprost isopropyl ester;

also referred to herein as bimatoprost free acid;

also referred to herein as travoprost;

also referred to herein as travoprost free acid or fluprostenol;

also referred to herein as latanoprost;

also referred to herein as latanoprost free acid;

also referred to herein as tafluprost;

also referred to herein as tafluprost free acid or AFP-172;

also referred to herein as CAY10509;and

also referred to herein as CAY10509 free acid;and 9-, 11-, and/or 15-ester derivatives (e.g., prodrugs) of the above,e.g., of formula:

wherein:

R₁ is —O(CO)R₆ and R₂ is —OH, or

R₁ is —OH, R₂ is —O(CO)R₆, or

R₁ is —OH, R₂ is —OH, and R₃ is —O(CO)R₈, or

R₁ is —OH, R₂ is —O(CO)R₆, and R₃ is —OH, or

R₁ is —O(CO)R₆, R₂ is —O(CO)R₆, and R₃ is —OH, or

R₁ is —O(CO)R₆, R₂ is —OH, and R₃ is —O(CO)R₈, or

R₁ is —OH, R₂ is —O(CO)R₆, and R₃ is —O(CO)R₈, or

R₁ is —O(CO)R₆, R₂ is —O(CO)R₆, and R₃ is —O(CO)R₈,

wherein R₆ and R₈ are as defined herein, and pharmaceutically acceptablesalts, hydrates, solvates, stereoisomers, polymorphs, tautomers,isotopically enriched derivatives, and prodrugs thereof. In certainembodiments, R₈ is —(CH₂)_(g)CH₃ wherein q is 0, 1, 2, 3, 4, 5, or 6,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃. In certainembodiments, R₆ is —(CH₂)_(r)CH₃ wherein r is 0, 1, 2, 3, 4, 5, or 6,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃.

In certain embodiments, the compound of Formula (I) is selected from thegroup consisting of latanoprost, latanoprost free acid, tafluprost,tafluprost free acid, travoprost, fluprostenol, bimatoprost, bimatoprostfree acid, and pharmaceutically acceptable salts, hydrates, solvates,stereoisomers, polymorphs, tautomers, isotopically enriched derivatives,and prodrugs thereof. In certain embodiments, the compound of Formula(I) is selected from the group consisting of latanoprost, latanoprostfree acid, tafluprost, tafluprost free acid, and pharmaceuticallyacceptable salts, hydrates, solvates, stereoisomers, polymorphs,tautomers, isotopically enriched derivatives, and prodrugs thereof. Incertain embodiments, the compound of Formula (I) is selected from thegroup consisting of latanoprost and pharmaceutically acceptablehydrates, solvates, stereoisomers, polymorphs, tautomers, isotopicallyenriched derivatives, and prodrugs thereof. In certain embodiments, thecompound of Formula (I) is selected from the group consisting oflatanoprost free acid and pharmaceutically acceptable salts, hydrates,solvates, stereoisomers, polymorphs, tautomers, isotopically enrichedderivatives, and prodrugs thereof. In certain embodiments, the compoundof Formula (I) is latanoprost. In certain embodiments, the compound ofFormula (I) is selected from the group consisting of tafluprost andpharmaceutically acceptable hydrates, solvates, stereoisomers,polymorphs, tautomers, isotopically enriched derivatives, and prodrugsthereof. In certain embodiments, the compound of Formula (I) is selectedfrom the group consisting of tafluprost free acid and pharmaceuticallyacceptable salts, hydrates, solvates, stereoisomers, polymorphs,tautomers, isotopically enriched derivatives, and prodrugs thereof. Incertain embodiments, the compound of Formula (I) is tafluprost.

Exemplary compounds of Formula (II) include, but are not limited to,

also referred to as AL-12182;

also referred to as AL-12182 free acid;and ester derivatives (e.g., prodrugs) of the above, e.g., of formula:

wherein:

R₁ is —OH and R₃ is —O(CO)R₈, or

R₁ is —O(CO)R₆, and R₃ is —OH, or

R₁ is —O(CO)R₆, and R₃ is —O(CO)R₈,

wherein R₆ and R₈ are as defined herein, and pharmaceutically acceptablesalts, hydrates, solvates, stereoisomers, polymorphs, tautomers,isotopically enriched derivatives, and prodrugs thereof. In certainembodiments, R₈ is —(CH₂)_(g)CH₃ wherein q is 0, 1, 2, 3, 4, 5, or 6,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃. In certainembodiments, R₆ is —(CH₂)_(r)CH₃ wherein r is 0, 1, 2, 3, 4, 5, or 6,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃.

In certain embodiments, the compound of Formula (I) or (II) is a prodrugof any one of the compounds described herein. Exemplary prodrugs includeesters, amides, and/or thioamides of the parent free acid, and compoundswherein a hydroxyl group on the parent compound (e.g., a pentacyclichydroxyl group R₁ and/or R₂ or the hydroxyl group at the R₃ and/or R₃′position) is esterified, e.g., 9-, 11-, and/or 15-ester derivatives asdescribed herein, e.g., wherein the ester at said position is a C₁₋₆ester, e.g., 9-propionyl bimatoprost, 11-propionyl bimatoprost,15-propionyl bimatoprost, 9-butyryl bimatoprost, 11-butyryl bimatoprost,15-butyryl bimatoprost, and the like.

Compositions and Formulations

In certain embodiments, the present invention provides compositions fortopical administration of a composition comprising a PFPRA compound, asdescribed herein, and a fatty acid, e.g., oleic acid.

In certain embodiments, the composition further comprises an organicalcohol. In some embodiments, the composition further comprises aviscosity-enhancing agent. In certain embodiments, the compositionfurther comprises an antioxidant. In certain embodiments, thecomposition is a solution. In certain embodiments, the composition isnot irritating to the skin.

In some embodiments, the PFPRA compound is a compound of Formula (I) or(II), or a pharmaceutically acceptable salt, hydrate, solvate,stereoisomer, polymorph, tautomer, isotopically enriched derivative, orprodrug thereof. In some embodiments, the PFPRA compound is latanoprost,tafluprost, travoprost, or bimatoprost, or a pharmaceutically acceptablesalt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopicallyenriched derivative, or prodrug thereof. In certain embodiments, thePFPRA compound is selected from the group consisting of latanoprost,latanoprost free acid, tafluprost, tafluprost free acid, andpharmaceutically acceptable salts, hydrates, solvates, stereoisomers,polymorphs, tautomers, isotopically enriched derivatives, and prodrugsthereof. In certain embodiments, the PFPRA compound is selected from thegroup consisting of latanoprost and pharmaceutically acceptablehydrates, solvates, stereoisomers, polymorphs, tautomers, isotopicallyenriched derivatives, and prodrugs thereof. In certain embodiments, thePFPRA compound is selected from the group consisting of latanoprost freeacid and pharmaceutically acceptable salts, hydrates, solvates,stereoisomers, polymorphs, tautomers, isotopically enriched derivatives,and prodrugs thereof. In certain embodiments, the PFPRA compound isselected from the group consisting of tafluprost and pharmaceuticallyacceptable hydrates, solvates, stereoisomers, polymorphs, tautomers,isotopically enriched derivatives, and prodrugs thereof. In certainembodiments, the PFPRA compound is selected from the group consisting oftafluprost free acid and pharmaceutically acceptable salts, hydrates,solvates, stereoisomers, polymorphs, tautomers, isotopically enrichedderivatives, and prodrugs thereof. In certain embodiments, the PFPRAcompound is latanoprost. In certain embodiments, the PFPRA compound istafluprost. In certain embodiments, the PFPRA compound hydrolyzes to anactive metabolite (e.g., the free acid of latanoprost, tafluprost,travoprost, or bimatoprost) upon administration to the skin.

In some embodiments, the final concentration of the PFPRA compoundprovided in the composition is between about 0.0001 percent and about 1percent (by weight), inclusive. In some embodiments, the finalconcentration is between about 0.001 percent and about 1 percent, 0.001and about 0.003 percent, about 0.001 and about 0.01 percent, about 0.003and about 0.01 percent, about 0.01 and about 0.03 percent, about 0.01and about 0.1 percent, about 0.03 and about 0.1 percent, about 0.1 andabout 0.3 percent, about 0.1 and about 1 percent, about 0.05 percent andabout 0.5 percent, or about 0.3 and about 1 percent (by weight),inclusive. These percentages are expressed by weight of the total weightof the composition.

In some embodiments, the final concentration of the fatty acid isbetween about 1 percent to about 20 percent by weight, inclusive. Insome embodiments, the final concentration of the fatty acid is betweenabout 5 and about 15 percent, about 1 and about 10 percent, about 1 andabout 2 percent, about 1 and about 3 percent, about 1 and about 5percent, about 2 and about 4 percent, about 3 and about 5 percent, about3 and about 7 percent, about 4 and about 6 percent, about 5 and about 7percent, about 6 and about 8 percent, about 7 and about 10 percent,about 10 and about 20 percent, about 10 and about 15 percent, or about15 and about 20 percent, inclusive. In certain embodiments, the finalconcentration of the fatty acid is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or 20 percent by weight. In someembodiments, the fatty acid is oleic acid and the final concentration ofthe oleic acid is between about 1 percent to about 20 percent by weight,inclusive. In some embodiments, the final concentration of the oleicacid is between about 5 and about 15 percent, about 1 and about 10percent, about 1 and about 2 percent, about 1 and about 3 percent, about1 and about 5 percent, about 2 and about 4 percent, about 3 and about 5percent, about 3 and about 7 percent, about 4 and about 6 percent, about5 and about 7 percent, about 6 and about 8 percent, about 7 and about 10percent, about 10 and about 20 percent, about 10 and about 15 percent,or about 15 and about 20 percent, inclusive. In certain embodiments, thefinal concentration of the oleic acid is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 percent by weight. Thesepercentages are expressed by weight of the total weight of thecomposition.

In some embodiments, the composition further comprises an organicalcohol, e.g., methanol, ethanol, propanol, isopropanol, 1,3-butanediol,ethylene glycol, or propylene glycol, or mixture thereof. In someembodiments, the composition comprises a PFPRA compound, a fatty acid(e.g., oleic acid), and ethanol. In some embodiments, the compositioncomprises a PFPRA compound, a fatty acid (e.g., oleic acid), andpropylene glycol. In some embodiments, the composition is a solutioncomprising a PFPRA compound, a fatty acid (e.g., oleic acid), propyleneglycol, and ethanol. In certain embodiments, the composition consistsessentially of the above recited components. In some embodiments, thecomposition comprises latanoprost, a fatty acid (e.g., oleic acid), andethanol. In some embodiments, the composition comprises latanoprost, afatty acid (e.g., oleic acid), and propylene glycol. In someembodiments, the composition is a solution comprising latanoprost, afatty acid (e.g., oleic acid), propylene glycol, and ethanol. In certainembodiments, the composition consists essentially of the above recitedcomponents. In some embodiments, the composition comprises tafluprost, afatty acid (e.g., oleic acid), and ethanol. In some embodiments, thecomposition comprises tafluprost, a fatty acid (e.g., oleic acid), andpropylene glycol. In some embodiments, the composition is a solutioncomprising tafluprost, a fatty acid (e.g., oleic acid), propyleneglycol, and ethanol. In certain embodiments, the composition consistsessentially of the above recited components.

In some embodiments, the composition comprises an organic alcohol whichacts as a base excipient (i.e., constituting the major component of theformulation, such as for example, provided in greater than 50% byweight). In some embodiments, the final concentration of the organicalcohol base excipient is between about 40 percent and about 99.5percent by weight, inclusive. In some embodiments, the finalconcentration of the organic alcohol base excipient is greater than 50percent and about 99 percent by weight, inclusive. In some embodiments,the final concentration of the organic alcohol base excipient is betweenabout 51 percent and 60 percent, 51 percent and about 70 percent, about60 percent and about 70 percent, about 60 percent and about 80 percent,about 70 percent and about 80 percent, about 70 percent and about 90percent, about 80 percent and about 90 percent, about 85 percent andabout 95 percent, about 90 percent and about 95 percent, about 90percent and about 99 percent, and about 95 percent and about 99 percent,inclusive. In certain embodiments, the organic alcohol which acts as abase excipient is ethanol. In these embodiments, the final concentrationof the ethanol base excipient is between about 51 percent and 60percent, 51 percent and about 70 percent, about 60 percent and about 70percent, about 60 percent and about 80 percent, about 70 percent andabout 80 percent, about 70 percent and about 90 percent, about 80percent and about 90 percent, about 85 percent and about 95 percent,about 90 percent and about 95 percent, about 90 percent and about 99percent, and about 95 percent and about 99 percent, inclusive. Thesepercentages are expressed by weight of the total weight of thecomposition.

In some embodiments, the composition comprises water. The water may be,for example, tap water, distilled water, or deionized water. In someembodiments, the final concentration of water is between about 0.1percent and about 30 percent by weight, inclusive. In some embodiments,the final concentration of water is between about 0.1 percent and 25percent, about 0.2 percent and about 20 percent, about 0.3 percent andabout 15 percent, about 0.4 percent and about 10 percent, about 0.5percent and about 8 percent, about 1 percent and about 5 percent,inclusive. In certain embodiments, the water replaces part of theorganic alcohol (such as ethanol) which acts as the base component ofthe composition.

In some embodiments, the composition comprises glycerin, i.e., glycerol.In some embodiments, the final concentration of glycerin is betweenabout 0.1 percent and about 30 percent by weight, inclusive. In someembodiments, the final concentration of glycerin is between about 0.1percent and 25 percent, about 0.2 percent and about 20 percent, about0.3 percent and about 15 percent, about 0.4 percent and about 10percent, about 0.5 percent and about 8 percent, about 1 percent andabout 5 percent, inclusive. In certain embodiments, the glycerinreplaces part of the organic alcohol (such as ethanol) which acts as thebase component of the composition.

In some embodiments, the composition comprises an organic alcohol whichis not the base component of the composition (e.g., provided as acomponent in 50% or less by weight). In certain embodiments, the finalconcentration of the organic alcohol is between about 5 percent andabout 50 percent by weight, inclusive. In some embodiments, the finalconcentration of the organic alcohol is between about 5 percent and 10percent, about 5 percent and about 15 percent, about 10 percent andabout 15 percent, about 10 percent and about 20 percent, about 15percent and about 20 percent, about 15 percent and about 25 percent,about 20 percent and about 25 percent, about 20 percent and 30 percent,about 25 percent and about 30 percent, about 25 percent and about 35percent, about 30 percent and about 35 percent, about 30 percent andabout 40 percent, about 35 percent and about 40 percent, about 35percent and about 45 percent, about 40 percent and about 50 percent,about 40 percent and about 45 percent, or about 45 percent and about 50percent, inclusive. In certain embodiments, the composition comprises anorganic alcohol in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% byweight. In certain embodiments, the organic alcohol is propylene glycol.In these embodiments, the final concentration of the propylene glycol isbetween about 5 percent and 10 percent, about 5 percent and about 15percent, about 10 percent and about 15 percent, about 10 percent andabout 20 percent, about 15 percent and about 20 percent, about 15percent and about 25 percent, about 20 percent and about 25 percent,about 20 percent and 30 percent, about 25 percent and about 30 percent,about 25 percent and about 35 percent, about 30 percent and about 35percent, about 30 percent and about 40 percent, about 35 percent andabout 40 percent, about 35 percent and about 45 percent, about 40percent and about 50 percent, about 40 percent and about 45 percent, orabout 45 percent and about 50 percent, inclusive. In certainembodiments, the composition comprises propylene glycol in 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, or 30% by weight.

In certain embodiments, the composition comprises:

(a) a PFPRA compound (e.g., latanoprost or tafluprost) in aconcentration of between about 0.0001 percent and about 1 percent (byweight), such as 0.001 and about 0.003 percent, about 0.001 and about0.01 percent, about 0.003 and about 0.01 percent, about 0.01 and about0.03 percent, about 0.01 and about 0.1 percent, about 0.03 and about 0.1percent, about 0.1 and about 0.3 percent, about 0.1 and about 1 percent,about 0.05 percent and about 0.5 percent, or about 0.3 and about 1percent (by weight), inclusive; and

(b) a fatty acid (e.g., oleic acid) in a concentration of between about1 percent to about 20 percent by weight, such as between about 5 andabout 15 percent, about 1 and about 10 percent, about 1 and about 2percent, about 1 and about 3 percent, about 1 and about 5 percent, about2 and about 4 percent, about 3 and about 5 percent, about 3 and about 7percent, about 4 and about 6 percent, about 5 and about 7 percent, about6 and about 8 percent, about 7 and about 10 percent, about 10 and about20 percent, about 10 and about 15 percent, or about 15 and about 20percent, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20 percent by weight, inclusive.

In certain embodiments, the composition comprises:

(a) a PFPRA compound (e.g., latanoprost or tafluprost) in aconcentration of between about 0.0001 percent and about 1 percent (byweight), such as 0.001 and about 0.003 percent, about 0.001 and about0.01 percent, about 0.003 and about 0.01 percent, about 0.01 and about0.03 percent, about 0.01 and about 0.1 percent, about 0.03 and about 0.1percent, about 0.1 and about 0.3 percent, about 0.1 and about 1 percent,about 0.05 percent and about 0.5 percent, or about 0.3 and about 1percent (by weight), inclusive;

(b) a fatty acid (e.g., oleic acid) in a concentration of between about1 percent to about 20 percent by weight, such as between about 5 andabout 15 percent, about 1 and about 10 percent, about 1 and about 2percent, about 1 and about 3 percent, about 1 and about 5 percent, about2 and about 4 percent, about 3 and about 5 percent, about 3 and about 7percent, about 4 and about 6 percent, about 5 and about 7 percent, about6 and about 8 percent, about 7 and about 10 percent, about 10 and about20 percent, about 10 and about 15 percent, or about 15 and about 20percent, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20 percent by weight, inclusive; and

(c) an organic alcohol (e.g., ethanol) in a concentration of betweenabout 51 percent and 60 percent, 51 percent and about 70 percent, about60 percent and about 70 percent, about 60 percent and about 80 percent,about 70 percent and about 80 percent, about 70 percent and about 90percent, about 80 percent and about 90 percent, about 85 percent andabout 95 percent, about 90 percent and about 95 percent, about 90percent and about 99 percent, and about 95 percent and about 99 percent,inclusive.

In certain embodiments, the composition comprises:

(a) a PFPRA compound (e.g., latanoprost or tafluprost) in aconcentration of between about 0.0001 percent and about 1 percent (byweight), such as 0.001 and about 0.003 percent, about 0.001 and about0.01 percent, about 0.003 and about 0.01 percent, about 0.01 and about0.03 percent, about 0.01 and about 0.1 percent, about 0.03 and about 0.1percent, about 0.1 and about 0.3 percent, about 0.1 and about 1 percent,about 0.05 percent and about 0.5 percent, or about 0.3 and about 1percent (by weight), inclusive;

(b) a fatty acid (e.g., oleic acid) in a concentration of between about1 percent to about 20 percent by weight, such as between about 5 andabout 15 percent, about 1 and about 10 percent, about 1 and about 2percent, about 1 and about 3 percent, about 1 and about 5 percent, about2 and about 4 percent, about 3 and about 5 percent, about 3 and about 7percent, about 4 and about 6 percent, about 5 and about 7 percent, about6 and about 8 percent, about 7 and about 10 percent, about 10 and about20 percent, about 10 and about 15 percent, or about 15 and about 20percent, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20 percent by weight, inclusive; and

(c) an organic alcohol (e.g., propylene glycol) in a final concentrationof between about 5 percent and about 50 percent by weight, such asbetween about 5 percent and 10 percent, about 5 percent and about 15percent, about 10 percent and about 15 percent, about 10 percent andabout 20 percent, about 15 percent and about 20 percent, about 15percent and about 25 percent, about 20 percent and about 25 percent,about 20 percent and 30 percent, about 25 percent and about 30 percent,about 25 percent and about 35 percent, about 30 percent and about 35percent, about 30 percent and about 40 percent, about 35 percent andabout 40 percent, about 35 percent and about 45 percent, about 40percent and about 50 percent, about 40 percent and about 45 percent, orabout 45 percent and about 50 percent, such as1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27, 28, 29, or 30% by weight, inclusive.

In certain embodiments, the composition comprises:

(a) a PFPRA compound (e.g., latanoprost or tafluprost) in aconcentration of between about 0.0001 percent and about 1 percent (byweight), such as 0.001 and about 0.003 percent, about 0.001 and about0.01 percent, about 0.003 and about 0.01 percent, about 0.01 and about0.03 percent, about 0.01 and about 0.1 percent, about 0.03 and about 0.1percent, about 0.1 and about 0.3 percent, about 0.1 and about 1 percent,about 0.05 percent and about 0.5 percent, or about 0.3 and about 1percent (by weight), inclusive;

(b) a fatty acid (e.g., oleic acid) in a concentration of between about1 percent to about 20 percent by weight, such as between about 5 andabout 15 percent, about 1 and about 10 percent, about 1 and about 2percent, about 1 and about 3 percent, about 1 and about 5 percent, about2 and about 4 percent, about 3 and about 5 percent, about 3 and about 7percent, about 4 and about 6 percent, about 5 and about 7 percent, about6 and about 8 percent, about 7 and about 10 percent, about 10 and about20 percent, about 10 and about 15 percent, or about 15 and about 20percent, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20 percent by weight, inclusive;

(c) a first organic alcohol (e.g., ethanol) in a concentration ofbetween about 51 percent and 60 percent, 51 percent and about 70percent, about 60 percent and about 70 percent, about 60 percent andabout 80 percent, about 70 percent and about 80 percent, about 70percent and about 90 percent, about 80 percent and about 90 percent,about 85 percent and about 95 percent, about 90 percent and about 95percent, about 90 percent and about 99 percent, and about 95 percent andabout 99 percent, inclusive; and

(d) a second organic alcohol (e.g., propylene glycol) in a finalconcentration of between about 5 percent and about 50 percent by weight,such as between about 5 percent and 10 percent, about 5 percent andabout 15 percent, about 10 percent and about 15 percent, about 10percent and about 20 percent, about 15 percent and about 20 percent,about 15 percent and about 25 percent, about 20 percent and about 25percent, about 20 percent and 30 percent, about 25 percent and about 30percent, about 25 percent and about 35 percent, about 30 percent andabout 35 percent, about 30 percent and about 40 percent, about 35percent and about 40 percent, about 35 percent and about 45 percent,about 40 percent and about 50 percent, about 40 percent and about 45percent, or about 45 percent and about 50 percent, such as1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27, 28, 29, or 30% by weight, inclusive.

In certain embodiments, the composition comprises a PFPRA compound(e.g., latanoprost or tafluprost), oleic acid in about 3% by weight, andan organic alcohol (e.g., propylene glycol or ethanol) in about 27% byweight.

In some embodiments, the composition further comprises a viscosityenhancing agent. A viscosity-enhancing agent, as used herein, is asubstance which increases the viscosity of a solution or liquid/solidmixture. Exemplary viscosity enhancing agents include, but are notlimited to, glycerin; cellulose derivatives (e.g., methylcellulose (MC);hydroxypropylmethylcellulose (HPMC); carboxymethylcellulose (CMC);microcrystalline cellulose (CC); ethyl cellulose; hydroxyethyl cellulose(HEC); hydroxypropyl cellulose (HPC); cellulose); gelatin; starch;hetastarch; poloxamers; pluronics; sodium CMC; sorbitol; acacia;povidone; carbopol; polycarbophil; chitosan; alginate; chitosanglutamate; hyaluronic acid; elastin; hyaluronan; maltodextrin DE;deoxyglycocholate (GDC); polymethacrylic acid; glycols (e.g.,polymethylene glycol; polyethylene glycol); cyclodextrins (e.g.,sulfobutylether B cyclodextrin); sodium tauro-dihydrofusidate (STDHF);and N-trimethyl chitosan chloride (TMC). In certain embodiments, theviscosity enhancing agent is a cellulose derivative, e.g., hydroxypropylcellulose (HPC). In certain embodiments, the composition comprises aviscosity enhancing agent between about 0.5% and about 5% by weight,inclusive. In certain embodiments, the composition comprises a viscosityenhancing agent in between about 0.5% and about 4%, between about 0.5%and about 3%, between about 0.5% and about 2%, between about 0.5% andabout 1%, between about 0.8% and about 5%, between about 0.8% and about4%, between about 0.8% and about 3%, between about 0.5% and about 2%, orbetween about 0.5% and about 1%, inclusive. In certain embodiments, thecomposition comprises a viscosity enhancing agent in about 0.5%, 0.6%,0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, or 5% (by weight). In certainembodiments, the viscosity enhancing agent is hydroxypropyl celluloseand the composition comprises hydroxypropyl cellulose in between about0.5% and about 4%, between about 0.5% and about 3%, between about 0.5%and about 2%, between about 0.5% and about 1%, between about 0.8% andabout 5%, between about 0.8% and about 4%, between about 0.8% and about3%, between about 0.5% and about 2%, or between about 0.5% and about 1%,inclusive. In certain embodiments, the composition compriseshydroxypropyl cellulose in about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%,3%, 4%, or 5% (by weight). In certain embodiments, the compositioncomprises hydroxypropylcellulose in about 1% by weight.

In certain embodiments, the composition further comprises anantioxidant, e.g., alpha tocopherol, ascorbic acid, acorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol,potassium metabisulfite, propionic acid, propyl gallate, sodiumascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.In certain embodiments, the composition comprises an antioxidant betweenabout 0.001% and about 0.1% by weight, inclusive. In certainembodiments, the composition comprises an antioxidant in between about0.001% and about 0.05%, 0.001% and about 0.04%, 0.001% and about 0.03%,0.001% and about 0.02%, 0.001% and about 0.01%, inclusive. In certainembodiments, the composition comprises an antioxidant in about 0.001%,0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%,0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% byweight. In certain embodiments, the antioxidant is alpha tocopherol andthe composition comprises alpha tocopherol in between about 0.001% andabout 0.05%, 0.001% and about 0.04%, 0.001% and about 0.03%, 0.001% andabout 0.02%, 0.001% and about 0.01%, inclusive. In certain embodiments,the composition comprises alpha tocopherol in about 0.001%, 0.002%,0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%,0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% by weight. Incertain embodiments, the composition comprises alpha tocopherol in about0.002% by weight.

In certain embodiments, the composition may further comprise otherpharmaceutically acceptable excipients including, but not limited to,solvents, diluents or other liquid vehicles, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, lubricants and the like. General considerationsin the formulation and/or manufacture of topical compositions can befound, for example, in Remington's Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), andRemington: The Science and Practice of Pharmacy, ^(21st) Edition(Lippincott Williams & Wilkins, 2005).

Compositions can be prepared, packaged, and/or sold in bulk, as a singleunit dose, and/or as a plurality of single unit doses. As used herein, a“unit dose” is discrete amount of the composition comprising apredetermined amount of the PFPRA compound. The amount of the PFPRAcompound is generally equal to the dosage of the PFPRA compound whichwould be administered to a subject and/or a convenient fraction of sucha dosage such as, for example, one-half or one-third of such a dosage.

Relative amounts of the PFPRA compound, the pharmaceutically acceptableexcipient, and/or any additional ingredients in a composition will vary,depending upon the identity, size, and/or condition of the subjecttreated and further depending upon the route by which the composition isto be administered.

Other Features of Compositions

Pharmaceutically acceptable excipients used in the manufacture ofprovided compositions include inert diluents, dispersing and/orgranulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as coloring agents,coating agents, perfuming agents, and sunscreens may also be present inthe composition.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, etc., and combinations thereof.

Exemplary surface active agents and/or emulsifiers includelipids/natural emulsifiers (e.g. acacia, agar, alginic acid, sodiumalginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin,egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidalclays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminumsilicate]), long chain amino acid derivatives, high molecular weightalcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetinmonostearate, ethylene glycol distearate, glyceryl monostearate, andpropylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.carboxy polymethylene, polyacrylic acid, acrylic acid polymer, andcarboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylenesorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60],polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate[Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span65], glyceryl monooleate, sorbitan monooleate [Span 80]),polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45],polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and Solutol), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethyleneethers, (e.g. polyoxyethylene lauryl ether [Brij 30]),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, etc. and/or combinations thereof.

Exemplary binding agents include starch (e.g. cornstarch and starchpaste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghattigum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, celluloseacetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum),and larch arabogalactan), alginates, polyethylene oxide, polyethyleneglycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes,water, alcohol, etc., and/or combinations thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal. Chlorobutanol, for example, can beused as a preservative in an ointment formulation at a concentration of0.001% to 1% by weight (such as 0.5% per weight) of the total weight ofthe final composition.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an anti-oxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, etc., and combinations thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, etc., and combinations thereof.

Exemplary oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary oils include, but are not limited to, butylstearate, caprylic triglyceride, capric triglyceride, cyclomethicone,diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil,octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

A composition of the invention can be combined with, incorporated into,and/or delivered by means of a patch or dressing, which often have theadded advantage of providing controlled delivery of the PFPRA compoundto the body. Alternatively or additionally, the rate can be controlledby either providing a rate controlling membrane and/or by dispersing thePFPRA compound in a polymer matrix and/or gel.

The composition may further comprise one or more of the additionalingredients described herein. In some embodiments, the additionalingredient is a sunscreen, moisturizer, colorant, antibiotic,antifungal, antiviral, antifibrotic, anti-inflammatory, anesthetic,analgesic, vasoconstrictor, vasodilator, vitamin or mineral, orantioxidant.

Although the descriptions of compositions provided herein areprincipally directed to compositions that are suitable for topicaladministration to humans, it will be understood by the skilled artisanthat such compositions are generally suitable for administration toanimals of all sorts. Modification of compositions suitable foradministration to humans in order to render the compositions suitablefor administration to various animals is well understood, and theordinarily skilled veterinary pharmacologist can design and/or performsuch modification with ordinary experimentation. General considerationsin the formulation and/or manufacture of compositions can be found, forexample, in Remington: The Science and Practice of Pharmacy 21st ed.,Lippincott Williams & Wilkins, 2005.

Still further encompassed by the invention are kits comprising acomposition of the invention as described herein and instructions foruse. Kits provided may comprise a provided composition and a container(e.g., a tube, vial, ampoule, bottle, syringe, and/or dispenser package,or other suitable container).

Methods of Treatment and Use

As generally described herein, the compositions described herein arecontemplated useful in the reduction of subcutaneous fat in a subject inneed thereof. Methods of use and treatment include therapeutic methodsand cosmetic methods, as described herein. For example, in one aspect,provided is a method of reducing body fat in a subject, comprisingtopically administering a composition as described herein to a subjectin need thereof. In another aspect, provided is a composition of thepresent invention for use in method of reducing body fat in a subject.In another aspect, provided use of a composition of the presentinvention in the manufacture of a medicament for reducing body fat in asubject. In certain embodiments, the method is a therapeutic method. Incertain embodiments, the method is a cosmetic method.

Fat reduction can include reducing fat as measured by at least one ofvolume, size, mass, bulk, density, amount, and/or quantity. The presentinvention is expected to reduce fat by greater than or equal to 75%,greater than or equal to 70%, greater than or equal to 60%, greater thanor equal to 50%, greater than or equal to 40%, greater than or equal to30%, greater than or equal to 25%, greater than or equal to 20%, greaterthan or equal to 15%, greater than or equal to 10%, or greater than orequal to 5%. For example, fat reduction can also include reducing fatcell amount (for example, fat cell number), reducing fat cell volume,reducing fat cell maturation, and/or dedifferentiating a fat cell.

In certain embodiments, the body fat is local, e.g., concentrated on theface, chin, neck, arms, abdomen, chest, breast, buttocks, hips, thighs,legs, and/or knees.

In certain embodiments, the subject suffers from or is likely to sufferfrom obesity, excess fat on the breast, excess fat on the chin,gynecomastia, drug-induced obesity, hypothyroidism,pseudohypoparathyroidism, hypothalamic obesity, polycystic ovariandisease, depression, binge eating, postpartum obesity, obesityassociated with smoking cessation, Prader-Willi syndrome, Bardet-Biedlsyndrome, Cohen syndrome, Down syndrome, Turner syndrome, growth hormonedeficiency, growth hormone resistance, leptin deficiency or resistance,Cushing syndrome, pseudo-Cushing syndrome, hypertrophy of dorsocervicalfat/dorsocervical fat hypertrophy (“buffalo hump”), moon facies, HIVlipodystrophy, orbital fat prolapse, age-related descent of abnormalfat, other acquired lipodystrophy, familial lipodystrophy, lipoma,lipomatosis, or Madelung disease. In certain embodiments, the subjectsuffers from or is likely to suffer from obesity, gynecomastia, HIVlipodystrophy, lipoma, steatoblepharon, excess eyelid fat, excessperiorbital fat, or excess fat on the chin. In certain embodiments, thesubject has a cosmetic condition.

In certain embodiments, the subject suffers from or is likely to sufferfrom excess submental fat. Thus, in one aspect, provided is acomposition for use in for reducing fat in a subject suffering fromexcess submental fat. In another aspect, provided is a method oftreating excess submental fat in a subject, comprising topicallyadministering (e.g., applying to the submental skin of the subject) acomposition as described herein to a subject in need thereof. In anotheraspect, provided is a composition as described herein for use in amethod of treating excess submental fat in a subject. In another aspect,provided is use a composition as described herein in the manufacture ofa medicament for treating excess submental fat in a subject.

In certain embodiments, the subject suffers from or is likely to sufferfrom steatoblepharon. Thus, in one aspect, provided is a composition foruse in for reducing fat in a subject suffering from steatoblepharon. Inanother aspect, provided is a method of treating steatoblepharon in asubject, comprising topically administering (e.g., applying to an eyelidof the subject) a composition as described herein to a subject in needthereof. In another aspect, provided is a composition as describedherein for use in a method of treating steatoblepharon in a subject. Inanother aspect, provided is use a composition as described herein in themanufacture of a medicament for treating steatoblepharon in a subject.

As described herein, the route of administering is topical. In certainembodiments, the administering is to a body part selected from the groupconsisting of the face, chin, submental region, jowls, cheeks,periorbital skin, neck, arms, abdomen, chest, breast, buttocks, hips,thighs, legs, and knees.

In certain embodiments, the subject has excess body fat as a side effectof medication (e.g., for example, cortisol and analogs, corticosteroids,megace, sulfonylureas, anti-retrovirals, antidepressants, monoamineoxidase inhibitors, selective serotonin reuptake inhibitors, oralcontraceptives, insulin or a form of insulin, risperidone, clozapine,and thiazolidinediones).

In certain embodiments, the subject has excess body fat due to changesin hormonal status (e.g., as a result of physiologic changes such aspregnancy or menopause).

In certain embodiments, the subject with excess body fat is undergoingor has recently undergone smoking cessation.

In certain embodiments, the subject has body fat of cosmeticsignificance, for example, due to age-related orbital fat prolapse,excess submental fat, or descent of the malar fat pads.

This aspect of invention may also be useful as an adjunct to any ofvarious kinds of surgery and/or non-invasive therapy, whether used inthe pre-operative, peri-operative, or post-operative period. Theinvention further contemplates uses preceding abdominal, thoracic,oncologic, endocrine, neurologic, transplant, and dermatologic surgery,whereby surgical exposure may be improved; preceding or followingorthopedic procedures, whereby surgical exposure as well aspost-operative recovery may be improved; and preceding cosmeticprocedures using lasers, another type of radiation, thermal therapy,cryotherapy, ultrasound, electrolysis, chemical treatment and the like,e.g., skin tightening, skin resurfacing, collagen remodeling, and thelike.

Examples

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatthese compositions may also consist essentially of, or consist of, therecited components. Further, it should be understood that the order ofsteps or order for performing certain actions are immaterial so long asthe invention remains operable. Moreover, two or more steps or actionsmay be conducted simultaneously. In light of the foregoing description,the specific non-limiting examples presented below are for illustrativepurposes and not intended to limit the scope of the invention in anyway.

Example 1

A topical composition for local reduction of subcutaneous fat wasprepared as follows:

TABLE 1 Ingredients Amount Latanoprost 100 mg alpha-Tocopherol  2 mgEthanol, anhydrous 69.9 g Propylene glycol   27 g Oleic acid   3 gHydroxypropylcellulose (e.g., Klucel ® Grade HF)   1 g

Neat latanoprost was dissolved in ethanol. Propylene glycol and oleicacid were added, and the resulting preparation was thoroughly mixed.Hydroxypropylcellulose was added and thoroughly mixed to yield about 100grams of gel with a final latanoprost concentration of about 0.1% (w/w).

It was found during the course of the experiments with this and otherlatanoprost formulations that latanoprost (prodrug) was converted(hydrolyzed) to the active metabolite, latanoprost free acid, in theskin samples. See, e.g., Example 4.

Example 2

A composition was prepared according to Example 1. High PerformanceLiquid Chromatography (HPLC) verified the latanoprost concentration andlack of impurities. The composition was stored under long-term andaccelerated stability conditions (25° C./60% relative humidity and 45°C./75% relatively humidity, respectively). The composition wasreanalyzed and tested on HPLC at regular intervals for 6 months.Standard tests for microbial growth were also performed. At eachinterval, organoleptic inspection showed physical stability of thecomposition, and HPLC shows a stable latanoprost concentration and alack of known degradants (e.g., latanoprost free acid, 15-ketolatanoprost). Furthermore, no microbes were detected. Thus, it wasconcluded that the composition demonstrates excellent physical andchemical stability.

Example 3

A composition was prepared according to Example 1. The composition wassubjected to various harsh environmental conditions in an attempt tocause degradation. The presence of degradants or impurities was assessedusing a stability-indicating HPLC method, i.e., a method proven todetect known degradants of latanoprost. No degradation was observedfollowing exposure to intense ultraviolet light for 4 days or elevatedtemperature (75° C.) for 24 hours. Furthermore, the physicalcharacteristics of the composition were unchanged following exposure tolow temperature (−20° C.) for 24 hours (e.g., there was nosolidification or separation). Thus, it was concluded that thecomposition remains stable despite environmental stressors that canoccur during the storage and distribution of a commercial product.

Example 4

Skin permeation studies were conducted with various formulations oflatanoprost, ex vivo, on fresh human skin. Fresh human skin was obtainedfrom live donors undergoing abdominoplasty and mounted on a standard(Franz-type) diffusion cell apparatus. All test articles contained 0.8%(weight/weight) of latanoprost. Each test article (8 mg) was uniformlyapplied to a skin surface of 0.8 cm². All formulations were tested onskin from at least two different donors. Treated skin was left open tothe atmosphere to simulate clinical conditions. Receptor fluid flowedcontinuously over 24 hours and was collected in fractions. The amount ofactive drug metabolite (latanoprost free acid) in these fractions wasdetermined by Liquid Chromatography/Tandem Mass Spectrometry. Thefollowing amounts of drug were recovered from receptor fluid over 24hours:

TABLE 2 Formulation Drug mass (ng, mean) Ethanol 70%, PG 27%, oleic acid3% 7120 Ethanol 70%, PG 30% 3930 Ethanol 75%, DGME 25% 1260 Ethanol 75%,LL 25% 890 Ethanol 50%, LL 25%, DGME 25% 840 DMSO 99% Gel 5850Petrolatum 70%, PG 15%, PS 15% 2080 Petrolatum 87.5%, PG 7.5%, PS 5%1130 DGME = diethylene glycol monomethyl ether, DMSO =dimethylsulfoxide, LL = lauryl lactate, PG = propylene glycol, PS =polysorbate 80

Thus, a formulation of latanoprost comprising propylene glycol and oleicacid provided superior dermal drug penetration compared to a range ofother formulations and known enhancers, including DMSO, LL, and DGME.The superiority of the propylene glycol/oleic acid formulation over 99%DMSO was particularly surprising, because DMSO is considered a“universal solvent” with powerful skin penetration enhancement anddelivery accelerant properties (see, e.g., Patel et al., Penetrationenhancers for transdermal drug delivery system: a review, IJPI JPharmaceut Cosmetol; 2011; 5:53-65).

Example 5

Skin permeation studies were conducted with various formulations oflatanoprost 0.5%, ex vivo, on fresh human skin, as described in theforegoing example. All formulations comprised ethanol (70%) and oleicacid (1.5%, 3% or 4.5%) with the remainder essentially as propyleneglycol (28.5%, 27% or 25.5%, respectively). All studies were run induplicate. Mean 24-hour flux results were as follows:

TABLE 3 Latanoprost Flux Latanoprost Free Acid Flux Oleic acid content(ng/cm²/hr) (ng/cm²/hr) 1.5% 5.5 37.7   3% 7.4 60.1 4.5% 5.4 55.5

Thus, a formulation of latanoprost comprising 3% oleic acid providedsuperior dermal drug penetration compared to comparable formulationscomprising either 1.5% or 4.5% oleic acid. Furthermore, latanoprost(prodrug) was converted (hydrolyzed) to the active metabolite,latanoprost free acid, in the skin samples, a finding which was verifiedby recovery of latanoprost free acid (at large excess to latanoprost) inthe dermis and receptor fluid of each sample.

Example 6

Skin permeation studies were conducted with two formulations oflatanoprost 0.1% w/w, ex vivo, on fresh pig skin, by methods essentiallyas described in the foregoing example. All studies were run induplicate. Mean 12-hour flux results were as follows:

TABLE 4 Latanoprost Flux Latanoprost Free Acid Formulation (ng/cm²/hr)Flux (ng/cm²/hr) 99.9% petrolatum 0 9.7 Ethanol 69.9%, PG 0.24 26 27%,oleic acid 3%

Thus, a formulation of latanoprost comprising propylene glycol and 3%oleic acid provided superior dermal drug penetration compared to aformulation comprising 99.9% petrolatum.

Example 7

Skin permeation studies were conducted on compositions comprisinglatanoprost 0.5% in a vehicle consisting essentially of: (A) 70%ethanol, 27% PG, and 3% oleic acid; (B) 60% ethanol, 10% water, 27% PG,and 3% oleic acid; or (C) 45% ethanol, 25% water, 27% PG, and 3% oleicacid. The three vehicles were associated with similar penetration oflatanoprost and latanoprost free acid.

Example 8

Skin permeation studies were conducted on compositions comprisinglatanoprost 0.3% in a vehicles consisting essentially of: (D) 68%ethanol, 27% PG, 3% oleic acid and 2% hydroxypropylcellulose; (E) 58%ethanol, 27% PG, 10% glycerin, 3% oleic acid and 2%hydroxypropylcellulose; (F) and 68% ethanol, 18% PG, 10% glycerin, 2%oleic acid and 2% hydroxypropylcellulose. The three vehicles wereassociated with similar penetration of latanoprost and latanoprost freeacid.

Example 9

Formulations consisting of varying concentrations of latanoprost, PG27%, oleic acid 3%, hydroxypropylcellulose 1%, and ethanol q.s. (allw/w) were administered to the dorsal skin (400 cm²) of four Gottingenminipigs. On day 1, animals received 8 ml of a formulation comprisinglatanoprost 0.02% (w/w). On day 3, they received 8 ml of a formulationcomprising latanoprost 0.1% (w/w). On day 5, they received 8 ml of aformulation comprising latanoprost 0.5%. Throughout the study and untilday 7, animals were observed for skin condition and overall health andbehavior. The formulations were well tolerated on the skin, and noadverse reactions were observed.

Example 10

In two studies, Gottingen minipigs were treated with repeat doses oflatanoprost 0.1% or 0.5% in a formulation comprising 27% PG, oleic acid3%, and HPC 1% with the remainder as ethanol (Study 1; n=3 per group);or latanoprost 0.16% or 0.8% in pluronic lecithin organogel (Study 2;n=6 per group). All animals were treated the same application rate over10% of body surface area on the dorsal skin. Animals were monitored forskin condition, body weight, and safety. Twenty-four hours after thelast dose, animals were scarified, and drug (latanoprost plus LFA)concentrations were measured in local subcutaneous fat by carefuldissection of tissue, washing, homogenization, extraction, and liquidchromatography/tandem mass spectrometry (LC/MS/MS). As shown in thetable below, 0.1% latanoprost in a PG/oleic acid formulation achieveddrug concentration in subcutaneous fat similar to those achieved by 0.8%latanoprost in pluronic lecithin organogel. Furthermore, 0.5%latanoprost in a PG/oleic acid formulation achieved drug concentrationsabout 15 times higher that 0.8% latanoprost in pluronic lecithinorganogel. Furthermore, the PG/oleic acid formulations achieved theseresults after only 10 doses, whereas the pluronic lecithin organogelresults were after 42 doses. Thus, it was concluded that theformulations comprising oleic acid provided PFPRA drug delivery that wasabout one order of magnitude greater than pluronic lecithin organogel.

TABLE 5 Total drug in Formulation Duration fat (ug/g) 0.10% latanoprost27% PG, 3% OA, 10 days 4 1% HPC, 68.9% ethanol 0.50% latanoprost, 27%PG, 3% OA, 10 days 59 1% HPC, 68.5% ethanol 0.16% latanoprost, pluroniclecithin organogel 42 days 1 0.80% latanoprost, pluronic lecithinorganogel 42 days 4 HPC = hydroxypropylcellulose; OA = oleic acid; PG =propylene glycol

Example 11

Three formulations comprising ethanol, propylene glycol, and oleic acid(without active ingredients) were applied to skin on the volar forearmson healthy adult men and women (n=4). The application area was 5 cm×5cm. Application was once daily for 7 consecutive days. Skin conditionand participant experience were noted daily, with results as follows:

TABLE 6 Formulation (all included 70% ethanol plus 1% Skin ParticipantHydroxypropylcellulose) Condition Experience PG 25.5%, oleic acid 4.5%Normal Well-tolerated, (100%) aesthetically pleasing PG 27%, oleic acid3% Normal Well-tolerated, (100%) aesthetically pleasing PG 28.5%, oleicacid 1.5% Normal Well-tolerated, (100%) aesthetically pleasing PG =propylene glycol, PS = polysorbate 80

Thus, the above formulations comprising propylene glycol and oleic acidwere non-irritating when applied repeatedly to human skin.

Example 11

A composition consisting essentially of latanoprost 0.5%, ethanol 67%,propylene glycol 27%, oleic acid 3% (all w/w) was administered to thedorsal skin (10% of body surface area) of eight Gottingen minipigs, oncedaily for 13 weeks. An equal number of animals were treated with aplacebo composition, consisting essentially of ethanol 67%, propyleneglycol 27%, oleic acid 3% (all w/w). Animals were observed for safetyand tolerability. The compositions were well tolerated in all animals.After 13 weeks, animals were sacrificed and dorsal skin, fat, and musclewere dissected en bloc from a standardized portion of the treatmentarea. As compared to animals treated with the placebo composition, therewas gross atrophy, i.e., a thickness reduction of 30% to 70%, ofsubcutaneous fat in animals treated with the latanoprost 0.5% article.

Example 12

From the study described in Example 11, a portion of the tissue is fixedin formalin, stained with hematoxylin and eosin, and examinedhistopathologically. Subcutaneous fat thickness is measuredsystematically, for example by measuring the thickness of fat from thedermis to the panniculus carnosus using image analysis software such asImageJ (National Institutes of Health). From another portion of thetissue, subcutaneous fat is dissected, washed, pulverized, andhomogenized, with the homogenate submitted for quantification oflatanoprost free acid concentration using liquid chromatography withtandem mass spectrometry (a method known in the art). It is predictedthat the composition containing latanoprost will be associated withreduced subcutaneous fat thickness, as compared to control. It isfurther predicted that the latanoprost composition will be associatedwith amounts of latanoprost free acid in subcutaneous fat that areconsidered therapeutically effective, with reference to other in vivoexperiments and in vitro assays. It is further predicted that thelatanoprost composition of this example will be associated with highertissue concentrations of latanoprost free acid and/or higher degrees ofsubcutaneous fat reduction compared to other formulations hithertodisclosed.

Example 13

A composition comprising 27% PG, 3% oleic acid, 2%hydroxypropylcellulose, and ethanol, and optionally comprisinglatanoprost, was tested in a clinical trial. Patients (n=18) applied thecompositions to a 50 cm² area of skin once daily for 42 consecutivedays. Patients underwent serial skin exams and local and systemic safetyassessments. The compositions were well tolerated, and skin exams wereunremarkable. No systemic side effects were noted.

Example 14

Different compositions, comprising latanoprost 5 mM, are tested on obesemice. Mice approximately six weeks old, all with similar baseline bodymass, are randomized and prospectively treated as follows (n=5 animalsper group):

TABLE 7 Group Compound Formulation (w/w) A Vehicle only Ethanol 70%, PG30% B Vehicle only Ethanol 70%, PG 27%, oleic acid 3% C Latanoprost 5 mMEthanol about 69.8%, PG 30% D Latanoprost 5 mM Ethanol about 69.8%, PG27%, oleic acid 3%

The dose is 0.1 cc to the right flank, daily. Mice are fed ad libitumand weighed daily for about 28 days. On or about day 28, mice aresacrificed and samples of skin with subcutaneous fat are collected forhistologic examination.

It is predicted that after about 28 days, mice in Group D will showrelatively less weight gain (or more weight loss) and relatively lessadiposity compared to mice in any of Groups A, B, or C.

Thus, it is predicted that in a mouse model of obesity, the foregoingresults show superior reduction of adiposity with a latanoprostformulation comprising ethanol, propylene glycol, and oleic acid, ascompared to a comparable equimolar latanoprost formulation that islacking oleic acid.

Example 15

The following experiment describes a randomized, placebo-controlled,double-blind trial in human subjects to test whether the safety andefficacy of a PFPRA pharmaceutical composition for reduction ofsubmental fat. The composition can be, for example, as described inExample 1, wherein the PFPRA is latanoprost. Alternatively, the PFPRAcan be tafluprost. Other alternatives within the scope of the inventioncan also be used.

Eligible subjects (for example, n=60) with excess submental fat areentered into a randomized double-blind study. Subjects are randomized in1:1 fashion to receive either the active pharmaceutical composition (forexample, comprising latanoprost 0.1% to 0.5% or tafluprost 0.01% to0.1%, weight per total weight of the composition), or the correspondinginactive vehicle. Subjects are instructed to apply, once a day, ametered dose of 0.5 ml to the chin. Serial clinical assessments,photographs, and magnetic resonance imaging (MRI) scans are performedprior to the first dose and then at 6 and 12 weeks. Treatment continuesfor a total of 12 weeks. It is contemplated that over time, for exampleafter 12 weeks of treatment, the pharmaceutical composition comprisinglatanoprost (or tafluprost) will be associated with more reduction inthe depth and/or volume of submental fat, as measured by clinicalassessment and/or MRI, as compared to vehicle alone.

Example 16

The following experiment describes a randomized, placebo-controlled,double-blind trial in human subjects to test whether the safety andefficacy of a PFPRA pharmaceutical composition for reduction ofabdominal fat. The composition can be, for example, as described inExample 1, wherein the PFPRA is latanoprost. Alternatively, the PFPRAcan be tafluprost. Other alternatives within the scope of the inventioncan also be used.

Eligible subjects (for example, n=60) with excess anterior abdominal fatare entered into a randomized double-blind study. Subjects arerandomized in 1:1 fashion to receive either the active pharmaceuticalcomposition (for example, comprising latanoprost 0.1% to 0.5% ortafluprost 0.01% to 0.1%, weight per total weight of the composition),or the corresponding inactive vehicle.

Subjects are instructed to apply, once a day, a metered dose, forexample, of 2 ml over a 200 cm² application area on the anteriorabdomen. The application area is standardized, for example, by use of atemplate that is centered on the umbilicus.

Serial clinical assessments, subjective patient assessments,photographs, and magnetic resonance imaging (MRI) scans are performedprior to the first dose and then, for example, at 6 and 12 weeks.Treatment continues, for example, for a total of 12 weeks.

It is contemplated that over time, for example after 6 to 12 weeks oftreatment, the pharmaceutical composition comprising latanoprost (ortafluprost) will be associated with more reduction in the depth and/orvolume of subcutaneous fat under the treatment area, as measured byclinical assessment, subjective patient assessment, photographs, and/orMRI, as compared to vehicle alone. It is further contemplated thatsubjects treated with latanoprost or tafluprost will be more satisfiedwith their cosmetic appearance, compared to those treated with vehiclealone.

OTHER EMBODIMENTS

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1-18. (canceled)
 19. A composition comprising latanoprost and oleicacid.
 20. The composition of claim 19, wherein latanoprost concentrationis between about 0.05 percent and about 0.5 percent, inclusive, byweight of the total weight of the composition.
 21. The composition ofclaim 19, wherein the composition comprises between about 1 percent andabout 20 percent of oleic acid, inclusive, by weight of the total weightof the composition.
 22. The composition of claim 21, wherein thecomposition comprises between about 1 percent and about 5 percent oleicacid, inclusive, by weight of the total weight of the composition. 23.The composition of claim 22, wherein the composition comprises betweenabout 2 percent and about 4 percent oleic acid, inclusive, by weight ofthe total weight of the composition.
 24. The composition of claim 19,further comprising propylene glycol.
 25. The composition of claim 24,wherein the composition comprises between about 5 percent and about 50percent of propylene glycol, inclusive, by weight of the total weight ofthe composition.
 26. The composition of claim 25, wherein thecomposition comprises between about 20 percent and about 30 percent ofpropylene glycol, inclusive, by weight of the total weight of thecomposition.
 27. The composition of claim 26, wherein the compositioncomprises between about 25 percent and about 30 percent of propyleneglycol, inclusive, by weight of the total weight of the composition. 28.The composition of claim 27, wherein the composition comprises about 3percent oleic acid and about 27 percent propylene glycol by weight ofthe total weight of the composition.
 29. The composition of claim 19,further comprising ethanol.
 30. The composition of claim 29, wherein thecomposition comprises between about 60 percent and about 80 percentethanol, inclusive, by weight of the total weight of the composition.31. The composition of claim 19, further comprising glycerin.
 32. Amethod for reducing body fat in a subject in need thereof, the methodcomprising topically administering to the subject the composition ofclaim
 19. 33. A method for reducing body fat in a subject in needthereof, the method comprising topically administering to the subject acomposition comprising tafluprost and oleic acid.
 34. The method ofclaim 33, comprising tafluprost, wherein tafluprost concentration isbetween about 0.01 percent and about 0.1 percent, inclusive, by weightof the total weight of the composition.
 35. The method of claim 33,wherein the composition comprises between about 1 percent and about 20percent of oleic acid, inclusive, by weight of the total weight of thecomposition.
 36. The method of claim 33, wherein the composition furthercomprises propylene glycol.
 37. The method of claim 36, wherein thecomposition comprises between about 5 percent and about 50 percent ofpropylene glycol, inclusive, by weight of the total weight of thecomposition.